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YALE  UNIVERSITY 

MRS.   HEPSA  ELY  SILLIMAN  MEMORIAL 

LECTURES 


ORGANISM  AND  ENVIRONMENT  AS  ILLUSTRATED 
BY  THE  PHYSIOLOGY  OF  BREATHING 


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ORGANISM    AND    ENVIRON 

MENT   AS   ILLUSTRATED 

BY  THE   PHYSIOLOGY 

OF    BREATHING 


BY 

John  Scott  Haldane,  M.D.,  LL.D.,  F.R.S. 

Fellow  of  New   College^   Oxford 


NEW  HAVEN:    YALE  UNIVERSITY  PRESS 

LONDON:    HUMPHREY  MILFORD 

OXFORD  UNIVERSITY  PRESS 

MDCCCCXVII 


Copyright,  1917 
By  Yale  University  Press 


First  published,  February,  1917 


QT 


THE  SILLIMAN  FOUNDATION 

In  the  year  1883  a  legacy  of  eighty  thousand  dollars 
was  left  to  the  President  and  Fellows  of  Yale  College 
in  the  city  of  New  Haven,  to  be  held  in  trust,  as  a  gift 
from  her  children,  in  memory  of  their  beloved  and 
honored  mother,  Mrs.  Hepsa  Ely  Silliman. 

On  this  foundation  Yale  College  was  requested  and 
directed  to  establish  an  annual  course  of  lectures  de- 
signed to  illustrate  the  presence  and  providence,  the 
wisdom  and  goodness  of  God,  as  manifested  in  the 
natural  and  moral  world.  These  were  to  be  designated 
as  the  Mrs.  Hepsa  Ely  Silliman  Memorial  Lectures. 
It  was  the  belief  of  the  testator  that  any  orderly 
presentation  of  the  facts  of  nature  or  history  con- 
tributed to  the  end  of  this  foundation  more  effectively 
than  any  attempt  to  emphasize  the  elements  of  doctrine 
or  of  creed;  and  he  therefore  provided  that  lectures 
on  dogmatic  or  polemical  theology  should  be  excluded 
from  the  scope  of  this  foundation,  and  that  the  sub- 
jects should  be  selected  rather  from  the  domains  of 
natural  science  and  history,  giving  special  prominence 
to  astronomy,  chemistry,  geology,  and  anatomy. 

It  was  further  directed  that  each  annual  course 
should  be  made  the  basis  of  a  volume  to  form  part  of 
a  series  constituting  a  memorial  to  Mrs.  Silliman.  The 
memorial  fund  came  into  the  possession  of  the  Cor- 
poration of  Yale  University  in  the  year  1901 ;  and  the 
present  volume  constitutes  the  thirteenth  of  the  series 
of  memorial  lectures. 


go 


PREFACE 

Yale  University  did  me  the  great  honour  of  inviting 
me  to  deliver  the  Silliman  Lectures  for  1915.  Owing 
to  the  war  I  was  unable  to  give  the  lectures  in  the  ap- 
pointed year ;  and  I  must  first  of  all  thank  the  Univer- 
sity for  permitting  me  to  postpone  them  till  the  present 
time. 

The  subject  of  the  full  lectures,  as  they  will,  I  hope, 
before  long  appear  in  book  form  under  the  imprint  of 
the  Yale  University  Press,  is  the  Physiology  of  Breath- 
ing. Much  of  the  material  contained  in  them  is,  how- 
ever, of  a  technical  character,  hardly  suited  for  public 
lectures.  With  the  approval  of  the  President,  I  have 
therefore  delivered  the  following  four  public  lectures 
confined  to  points  of  more  general  interest,  the  nature 
of  which  is  indicated  by  the  title. 

John  Scott  Haldane. 
New  Haven,  October,  1916. 


CONTENTS 

PAGE 

Preface vii 

I.  The  Regulation  of  Breathing  ....       1 

Introduction. 

The  problem  presented  by  the  co-ordinated  main- 
tenance of  reactions  between  organism  and  environ- 
ment— Vitalistic  and  Mechanistic  attempts  at  explana- 
tion. 

The  elementary  facts  relating  to  breathing. 

The  respiratory  centre  and  the  blood. 

Alveolar  air  and  the  exact  regulation  of  its  C02 
percentage. 

Apnoea  and  hyperpnoea. 

Varying  frequency  of  breathing. 

Physiological  effects  of  varying  pressures  of  gases. 

Effects  of  deprivation  of  C02. 

Effects  of  air  of  confined  spaces  and  mines. 

Effects  of  breathing  compressed  air  in  diving  and 
tunnelling. 

Influence  of  the  vagus  nerves  in  breathing. 

Co-ordination  of  the  responses  to  central  and  periph- 
eral nervous  stimuli,  so  that  the  respiratory  apparatus 
acts  as  a  whole. 

II.  The   Readjustments   of   Regulation    in 

Acclimatisation  and  Disease  ...     27 

The  gases  of  the  blood. 

Oxyhaemoglobin  and  the  conditions  of  its  dissocia- 
tion. 

The  combinations  of  C02  in  the  blood  and  their 
dissociation. 

Effects  of  oxygenation  of  haemoglobin  on  the  disso- 
ciation of  C02. 


x  CONTENTS 

Exact  physiological  regulation  of  the  blood-gases. 

Evidence  that  C02  acts  physiologically  as  an  acid. 

Investigations  of  the  reaction  of  blood. 

Extreme  delicacy  of  the  physiological  regulation  of 
the  blood  reaction. 

Regulation  of  the  blood-reaction  by  the  lungs,  liver, 
and  kidneys. 

Effects  of  want  of  oxygen  on  the  breathing. 

High  balloon  ascents,  CO  poisoning,  and  mountain 
sickness. 

Acclimatisation  to  oxygen  want: — the  Anglo-Ameri- 
can Expedition  to  Pike's  Peak  in  1911. 

Acclimatisation  effects  of  oxygen  want  on  the 
breathing. 

Acclimatisation  effects  on  the  haemoglobin  percent- 
age and  blood-volume. 

Acclimatisation  effects  on  active  secretion  inwards  of 
oxygen  by  the  lungs. 

Factors  in  acclimatisation  to  want  of  oxygen. 

III.  Regulation  of  the  Environment,  Inter- 
nal and  External 61 

Further  analysis  of  oxygen  secretion  by  the  lungs. 

Secretion  of  oxygen  by  the  swim-bladder. 

Secretion  in  other  glands. 

Analogy  between  secretion  and  cell-nutrition. 

The  circulatory  regulation  of  carriage  of  oxygen 
and  C02. 

Regulation  by  vaso-motor  nervous  control. 

Evidence  that  this  control  depends  upon  the  metabo- 
lism of  the  tissues. 

Evidence  that  the  heart's  action  in  pumping  blood 
depends  on  the  same  conditions. 

Part  played  by  contraction  of  the  veins. 

The  blood  as  a  constant  internal  environment. 

Regulation  of  this  internal  environment  by  the  kid- 
neys. 


CONTENTS  xi 

Regulation  by  other  organs. 

Regulation  after  bleeding  and  transfusion. 

Regulation  of  the  external  environment. 

In  reality  the  constancy  of  the  internal  or  external 
environment  is  a  balance  between  disturbing  and  re- 
storing influences,  each  of  which  persists. 

The  ordinary  idea  of  "function"  in  an  organ  is  mis- 
leading. 

"Causes"  and  "stimuli."  Physiology  as  an  endless 
maze  of  causes. 

IV.  Organic  Regulation  as  the  Essence  of 
Life.  Inadequacy  of  Mechanistic 
and  vltalistic  conceptions     ...     89 

Examination  of  mechanistic  interpretation  of  regula- 
tion of  the  environment. 

Difference  between  an  organism  and  a  machine. 

Life  endures  actively  and  develops. 

In  life  the  whole  is  in  the  parts  and  the  past  is  in  the 
present.  Organism,  environment,  and  life-history  can- 
not be  separated. 

For  biology  life  and  not  matter  is  the  primary  reality. 

The  true  aims  and  methods  of  biology. 

Biology  an  exact  experimental  science. 

Relation  of  physiological  to  physical  and  chemical 
investigation  of  organisms. 

The  limitations  of  existing  physical  and  chemical 
conceptions. 

Inadequacy  of  vitalism. 

Vitalism  the  inevitable  accompaniment  of  attempted 
mechanistic  interpretations  of  life. 

Individual  life  as  part  of  a  wider  life. 

The  limitations  of  biological  conceptions. 

Science  and  religion. 

Index 123 


I 

THE  REGULATION  OF  BREATHING 

Animal  physiology  deals  with  the  activities  ob- 
served in  living  animals,  including  men;  but  under 
certain  limitations.  It  deals  in  the  first  place  with 
all  the  activities  which  are  unconscious,  such  as  diges- 
tion, circulation  of  the  blood,  secretion,  or  the  growth 
and  maintenance  of  the  tissues.  It  deals,  also,  with 
the  unconscious  element  in  conscious  action.  I  may, 
for  instance,  breathe  consciously,  or  move  my  pen  in 
writing,  or  hear  the  noise  which  it  makes ;  but  of  the 
details  involved  in  any  of  these  acts  I  have  no  direct 
consciousness.  They  are  only  revealed  by  experi- 
mental physiology.  Physiology  deals,  also,  with  the 
sensations,  impulses,  and  instincts  of  all  kinds  which 
appear  in  consciousness;  but  does  not  deal  with  the 
meaning  and  conscious  control  which  are  attached  to 
them.  It  does  not  deal  with  this  meaning  and  con- 
scious control  for  the  very  good  reason  that  the  facts 
relating  to  them  cannot  be  combined  with  the  other 
material  of  physiology  into  a  homogeneous  sys- 
tem of  scientific  knowledge.  If,  however,  the  mean- 
ing and  conscious  control  attached  to  sensation  and 
instinct  are  disregarded,  the  latter  can  be  treated  as  a 
part  of  physiology,  and  are  so  treated  by  physiologists. 

When  the  activities  included  as  physiological  are 


2  ORGANISM  AND  ENVIRONMENT 

regarded  as  a  whole,  it  is  evident  that  in  the  case  of 
any  given  organism  they  are  co-ordinated  in  such  a 
way  that  the  life  of  the  organism  tends  to  maintain 
itself  as  a  whole,  or  at  any  rate  to  fulfil  its  character- 
istic life-history.  This  applies  not  less  to  the  reactions 
between  the  organism  and  its  environment  than  to 
those  between  the  parts  of  the  organism.  In  the 
inorganic  world  as  ordinarily  observed  and  inter- 
preted we  find  no  such  co-ordinated  maintenance. 
How  are  we  to  understand  its  presence  in  the  organic 
world?  This  is  of  course  a  very  old  question;  but  I 
wish  to  reconsider  it  in  these  lectures  in  the  light, 
more  particularly,  of  the  very  rapid  advances  which 
have  been  made  during  the  last  few  years  in  the 
physiology  of  breathing. 

We  are  familiar  with  two  opposing  theories  as  to 
the  nature  of  the  co-ordination.  One  of  these  is  that 
known  as  vitalism,  which  assumes  that  within  the 
living  body  there  is  constantly  at  work  a  special  influ- 
ence, the  so-called  "vital  principle,"  which  guides  the 
blind  physical  and  chemical  reactions  which  would 
otherwise  play  havoc  with  the  organism.  The  other 
is  that  the  body  is  a  very  complex  and  delicate 
mechanism,  so  arranged  as  to  bring  about  the  co- 
ordination. According  to  one  school  this  mechanism 
is  the  result  of  natural  selection,  though  according 
to  another  its  origin  must  be  sought  in  special  creation. 
I  hope  to  be  able  to  convince  you  that  neither  the 
vitalistic  nor  the  mechanistic  theory  of  the  relation 
between   organism  and  environment  is   tenable,   and 


REGULATION  OF  BREATHING  3 

that  we  must  look  to  a  more  thorough  and  direct 
interpretation.1 

Breathing  is  a  form  of  physiological  activity  which 
goes  on  whether  we  are  conscious  of  it  or  not.  Only 
by  a  great  effort  can  we  suspend  it  for  30  or  40  sec- 
onds, and  any  hindrance  to  breathing  is  violently 
resisted.  Although  in  the  seventeenth  century  Mayow 
came  very  near  to  discovering  the  chemical  changes 
in  air  during  breathing,  it  was  not  till  the  latter  half 
of  the  eighteenth  century  that  these  changes  were 
understood.  Black  found  that  what  we  now  call 
carbon  dioxide  is  given  off  in  breathing,  and  Priestley 
found  that  what  we  now  call  oxygen  disappears  as 
such.  Lavoisier  put  these  and  many  other  facts 
together,  and  showed  that  just  as  in  ordinary  com- 
bustion of  carbonaceous  material,  so  in  connection 
with  respiration,  oxygen  combines  with  carbon  and 
hydrogen  to  form  carbon  dioxide  and  water,  and  to 
liberate  heat.  Hence  breathing  is  a  process  in  which 
the  essential  factors  are  the  conveyance  of  oxygen  into 
the  body,  and  the  removal  from  it  of  carbon  dioxide. 
Breathing  can  thus  be  compared  to  the  supply  of  air 
to  a  fire  and  the  carrying  off  by  the  air  of  the  products 
of  combustion. 

Subsequent  investigation  showed  that  the  oxidation 

1  It  has  been  suggested  to  me  that  if  a  convenient  label 
is  needed  for  the  doctrine  upheld  in  these  lectures  the  word 
"organicism"  might  be  employed.  This  word  was  formerly 
used  in  connection  with  the  somewhat  similar  teaching  of 
such  men  as  Bichat,  von  Baer,  and  Claude  Bernard.  Cf. 
G.  Delage,  L'Heredite,  Paris,  1903,  p.  435. 


4  ORGANISM  AND  ENVIRONMENT 

process  does  not  occur  to  any  appreciable  extent  in 
the  lungs,  but  in  the  living  tissues  of  the  body  gener- 
ally. Oxygen  is  taken  up  by  the  blood  in  the  lungs, 
and  thence  carried  by  the  circulation  to  every  part  of 
the  body,  the  blood  yielding  its  oxygen  to  the  tissues 
in  passing.  Similarly  the  carbon  dioxide  formed  is 
carried  by  the  blood  from  the  tissues  to  the  lungs, 
where  it  is  given  off  to  the  air  breathed. 

But  another  still  more  important  point,  often 
entirely  missed  in  popular  accounts  of  physiology,  has 
appeared  clearly.  Within  wide  limits  the  oxidation 
process  is  practically  independent  of  the  abundance  in 
supply  of  either  oxygen  or  food  material  to  the  body. 
The  amount  of  oxygen  in  the  air  breathed,  or  carried 
by  the  blood  to  the  tissues,  may  be  increased  greatly 
without  increasing  the  rate  of  oxidation;  and  even 
after  long  starvation  the  consumption  of  oxygen  per 
unit  of  body  weight  remains  about  the  same.  The 
oxidation  process  is  thus  evidently  very  closely  regu- 
lated. In  the  burning  of  a  fire  there  is  no  such  regu- 
lation unless  it  is  artificially  brought  about.  Although 
increase  in  the  breathing  does  not  cause  increase  in  the 
rate  of  oxidation,  yet  it  is  evident  that  increase  in 
breathing  and  in  the  rate  of  circulation  accompanies 
increase  in  the  rate  of  oxidation,  as  for  instance  during 
muscular  exertion.  Here  again  we  have  regulation 
coming  in,  but  this  time  it  is  regulation  of  the  air 
supply. 

To  account  for  the  regulation  the  vitalistic  theory 
presupposes  the  activity  of  the  "vital  principle"  as  a 
regulating  agent  which  controls  the  consumption  of 


REGULATION  OF  BREATHING  5 

oxygen  and  regulates  the  air-supply,  thus  playing  the 
part  of  a  stoker  who  regulates  the  supply  of  both 
fuel  and  air  to  a  furnace.  On  the  mechanistic  theory 
the  regulation  is  automatic,  and  due  to  the  working  of 
a  mechanism  connected  with  the  fire.  The  latter 
theory  is  of  course  the  orthodox  one  at  present.  It 
is  not,  however,  these  theories  which  I  wish  to  discuss 
in  these  lectures,  but  the  character  of  the  facts  which 
each  of  the  two  theories  is  an  attempt  to  explain. 
When  the  true  character  of  these  facts  is  realised  it 
seems  to  me  that  the  old  and  ever  recurring  contro- 
versy between  mechanists  and  vitalists  disappears. 

It  has  been  known  for  more  than  a  century  that 
breathing  is  dependent  on  the  integrity  of  a  very  small 
area  of  the  brain  in  the  medulla  oblongata.  When  this 
area,  known  as  the  respiratory  centre,  is  destroyed 
all  signs  of  co-ordinated  breathing  efforts  disappear. 
Severance  of  the  nervous  connections  between  this 
centre  and  the  various  respiratory  muscles  paralyses 
these  muscles ;  but  so  long  as  any  connections  are  left 
respiratory  efforts  continue,  and  do  so  after  severance 
of  the  connections  between  the  centre  and  the  higher 
parts  of  the  brain.  The  action  of  this  centre  came  to 
be  regarded  as  automatic,  inspiratory  and  expiratory 
impulses  being  alternately  discharged  from  the  centre 
down  the  motor  or  efferent  nerves  leading  to  the 
inspiratory  or  expiratory  muscles,  but  no  afferent 
impulses  being  required  to  liberate  these  rhythmic  dis- 
charges. It  was  also  found  about  the  same  time  that 
any  interference  with  the  supply  of  properly  aerated 
blood  to  the  centre  causes  greatly  increased  activity 


6  ORGANISM  AND  ENVIRONMENT 

of  the  centre.  A  further  very  significant  fact,  ob- 
served originally  by  Hook  in  the  seventeenth  century, 
but  forgotten  and  rediscovered  by  Rosenthal  in  1875, 
is  that  if  the  blood  in  the  lungs  is  over-aerated  by 
artificial  ventilation,  the  breathing  stops  for  a  time,  the 
condition  known  as  apnoea  being  established.  It 
seemed,  therefore,  that  just  as  increased  breathing,  or 
hyperpnoea,  is  due  to  defective  aeration  of  the  blood, 
so  apnoea  is  due  to  excessive  aeration.  This  interpre- 
tation of  apnoea  was  soon  challenged,  as  we  shall  see, 
but  was  firmly  established  by  an  ingenious  experiment 
of  Fredericq.  He  crossed  the  circulation  of  two 
animals,  so  that  the  blood  coming  from  the  lungs  of  the 
first  animal  passed  to  the  respiratory  centre  of  the 
second,  and  vice  versa.  It  was  then  found  that  when 
excessive  artificial  ventilation  was  applied  to  the  lungs 
of  the  first  animal  the  second  became  apnoeic,  or  vice 
versa ;  while  great  hyperpnoea  in  the  first  animal  was 
produced  by  the  stoppage  of  the  breathing  in  the 
second. 

When  aeration  of  the  blood  is  defective  in  the 
lungs  two  changes  in  the  arterial  blood  occur.  On 
the  one  hand  its  content  in  oxygen  becomes  less,  and 
on  the  other  hand  it  becomes  more  highly  charged 
with  carbon  dioxide.  Blood  which  is  not  aerated 
with  oxygen  has  a  dark  purple  tint,  contrasting  with 
the  bright  scarlet  of  fully  aerated  blood.  This  dif- 
ference in  colour  is  due  to  the  fact  that  haemoglobin, 
the  substance  which  gives  blood  its  colour  and  is 
contained  in  the  red  blood  corpuscles,  is  the  substance 
which  carries  nearly  the  whole  of  the  oxygen,  and 


REGULATION  OF  BREATHING  7 

changes  colour  from  a  dark  purple  to  bright  scarlet 
when  it  takes  up  oxygen.  The  oxygen  is  taken  up  in 
the  form  of  a  weak  chemical  combination,  the  com- 
pound having  the  property  of  being  stable  only  in 
presence  of  a  certain  concentration  of  free  oxygen, 
and  dissociating  rapidly  as  the  concentration  of  oxygen 
falls.  The  function  fulfilled  by  haemoglobin  as  a  car- 
rier of  oxygen  from  the  lungs  to  the  tissues  is  thus 
readily  intelligible,  as  well  as  the  difference  in  colour 
between  arterial  and  venous  blood.  Substances  in  the 
blood  combine  to  form  similar  readily  dissociable  com- 
pounds with  carbon  dioxide,  but  no  change  in  colour 
is  associated  with  this  process. 

Both  deficiency  of  oxygen  and  excess  of  carbon 
dioxide  in  the  air  were  found  to  produce  increase  in 
the  breathing,  and  till  recently  the  respective  parts 
played  by  oxygen  and  carbon  dioxide  in  regulating 
the  breathing  were  by  no  means  clear,  and  opinions 
on  the  subject  were  divided.  I  was  myself  led  to 
investigate  the  whole  subject  through  observations  on 
the  effects  of  air  vitiated  by  respiration  or  by  the  gases 
met  with  in  coal-mines  and  other  confined  spaces. 

When  air  highly  vitiated  by  respiration  or  combus- 
tion of  carbonaceous  material  is  breathed  the  amount 
of  air  inspired  or  expired  is  increased.  The  increase 
is  due  to  the  carbon  dioxide  in  the  air ;  for  when  this 
is  removed  there  is  no  increase  unless  the  deficiency  of 
oxygen  is  extreme.  The  effect  produced  on  the  breath- 
ing by  carbon  dioxide  in  the  inspired  air  increases  out 
of  proportion  to  increase  in  the  percentage  of  the  car- 
bon  dioxide.     This   fact  suggested  that  in   ordinary 


8  ORGANISM  AND  ENVIRONMENT 

breathing  the  ventilation  of  the  lungs  is  such  as  to 
keep  the  percentage  of  carbon  dioxide  approximately 
constant  in  the  air  which  is  in  close  contact  with  the 
blood  in  the  small  airspaces  or  alveoli  inside  the  lungs. 
If  this  is  so,  it  is  clear  that  the  nearer  the  percentage  of 
carbon  dioxide  (C02)  in  the  inspired  air  approaches 
that  in  the  lung  alveoli  the  greater  will  be  the  quantity 
of  air  which  must  be  breathed  in  order  to  keep  the 
lung  air  normal  in  composition. 

The  matter  was  investigated  a  few  years  ago  by 
Mr.  Priestley  and  myself.  We  found  that  a  sample 
of  the  alveolar  air  could  easily  be  obtained  by  catch- 
ing the  last  parts  of  a  deep  breath  expired  through  a 
tube,  and  that  for  any  individual  under  normal  condi- 
tions, the  percentage  of  C02  in  this  air  remains  prac- 
tically constant  during  rest.  On  the  other  hand  the 
percentage  of  oxygen  in  the  inspired  and  alveolar  air 
could  be  varied  within  wide  limits  without  affecting 
either  the  amount  of  air  breathed  or  the  percentage  of 
CO 2  in  the  alveolar  air.  It  was  only  when  the  oxygen 
percentage  fell  very  low  that  the  breathing  was 
increased.  The  percentage  of  C02  in  the  alveolar  air 
is  not  quite  the  same  in  different  individuals,  but  the 
average  is  5.6  per  cent  for  adult  men. 

When  air  containing  different  percentages  of  C02 
was  breathed  it  was  found  that  the  volume  of  air 
breathed  was  increased  to  such  an  extent  as  to  keep 
the  percentage  of  C02  in  the  alveolar  air  as  nearly  nor- 
mal as  possible.  Nevertheless  there  was  always  a 
very  slight  increase  in  the  alveolar  C02  percentage 
with  each  increase  in  the  breathing.    For  an  increase 


REGULATION  OF  BREATHING  9 

of  100  per  cent  in  the  ventilation  of  the  lungs  over 
the  normal  resting  ventilation  there  was  an  increase 
of  about  0.2  per  cent  in  the  C02  percentage  in  the 
alveolar  air.  Very  accurate  methods  of  sampling  and 
gas  analysis  were  of  course  needed  in  order  to  detect 
these  differences.  When  the  percentage  of  C02  in  the 
inspired  air  reaches  about  the  normal  percentage  in  the 
alveolar  air  there  is  extreme  panting.  With  higher 
percentages  a  point  is  soon  reached  where  the  C02 
begins  to  produce  abnormal  effects,  culminating  in 
loss  of  consciousness.  The  breathing  then  quiets  down 
to  a  large  extent,  and  this  quieting  down  of  the  breath- 
ing, as  observed  in  animals,  led  formerly  to  a  misinter- 
pretation of  the  effects  of  C02  on  the  breathing. 

If  the  breathing  is  by  voluntary  effort  forced  for  a 
time,  so  as  to  reduce  the  percentage  of  C02  in  the 
alveolar  air,  a  period  of  apnoea  results.  This  effect 
depends  entirely  on  the  reduction  of  the  percentage  of 
C02  in  the  alveolar  air,  for  if  the  inspired  air  con- 
tains about  5  per  cent  of  C02  it  is  impossible  to  pro- 
duce apnoea  by  forced  breathing,  since  under  these 
conditions  it  is  impossible  to  reduce  the  alveolar  C02 
percentage  below  normal.  Careful  observations  by 
Douglas  and  myself  showed  that  it  is  only  necessary  to 
reduce  the  alveolar  C02  percentage  by  0.2  per  cent  in 
order  to  produce  apnoea.  It  thus  appears  that  a  rise 
of  about  0.2  per  cent  in  the  alveolar  C02  percentage 
is  sufficient  to  double  the  breathing,  while  a  fall  of 
0.2  per  cent  produces  cessation  of  breathing. 

We  are  now  in  a  position  to  understand,  up  to  a 
certain  point,  how  the  breathing  is   regulated.     The 


10        ORGANISM  AND  ENVIRONMENT 

quantity  of  C02  brought  to  the  lungs  by  the  blood 
is  constantly  varying  in  accordance  with  varying 
states  of  bodily  activity.  For  instance  during  the 
exertion  of  walking  at  a  moderate  rate  the  quantity 
of  C02  brought  to  the  lungs  is  three  or  four  times 
what  it  is  during  rest.  If  the  breathing  did  not 
increase  correspondingly,  the  percentage  of  C02  in 
the  alveolar  air  would  rise,  and  loss  of  consciousness 
would  result.  But  with  the  slightest  rise  in  the  alveo- 
lar C02  percentage  the  breathing  begins  to  increase,, 
and  thus  keeps  down  the  alveolar  C02.  When,  there- 
fore, the  production  of  C02  is  three  times  what  it  is 
during  rest,  the  breathing  is  also  increased  to  nearly 
three  times  what  it  is  during  rest.  The  alveolar  C02 
percentage  rises,  it  is  true;  but  only  by  0.4  per  cent. 
This  slight  rise  produces,  as  we  have  seen;  an  increase 
of  200  per  cent  in  the  breathing,  so  that  the  increase 
in  breathing  is  almost  proportional  to  the  increase  in 
the  production  of  C02.  Analysis  of  the  alveolar  air, 
and  determination  of  the  C02  produced  and  volume 
of  air  breathed  during  rest  and  work  show  that  this 
explanation  works  out  in  practice,  provided  that  no 
disturbing  causes  come  in. 

As  the  oxygen  percentage  in  the  alveolar  air  runs 
parallel  with  the  C02  percentage,  it  is  evident  that 
regulation  of  the  oxygen  percentage  is  involved  in 
regulation  of  the  C02  percentage.  The  net  result  is 
that  both  the  percentage  of  oxygen  and  that  of  C02. 
in  the  alveolar  air  are  very  constant,  in  spite  of  great 
changes  in  the  amount  of  oxygen  consumed  and  C02 
given  off  by  the  body. 


REGULATION  OF  BREATHING  11 

There  is  no  doubt  that  it  is  through  the  blood  that 
slight  changes  in  the  C02  percentage  of  the  alveolar 
air  affect  the  respiratory  centre.  The  effects  of  these 
changes  are  equally  rapid  and  marked  when  all  the 
nervous  connections  between  the  lungs  and  the  respir- 
atory centre  are  severed. 

To  most  persons  it  must  come  as  a  surprise  that  the 
breathing  is  so  exactly  regulated.  Common  observa- 
tion shows  us  that  the  breathing  is  often  more  or  less 
interrupted  temporarily,  and  varies  in  frequency  or 
depth  at  different  times,  as  if  the  regulation  were  only 
rough.  We  also  know  that  breathing  is  under  volun- 
tary control,  and  there  is  a  popular  idea  that  by  spe- 
cial forms  of  training  in  breathing  we  can  improve 
the  aeration  of  the  blood  and  the  supply  of  oxygen  to 
the  body. 

If  samples  of  the  alveolar  air  are  taken  it  is  found 
that  they  only  give  a  constant  percentage  of  C02  if 
the  breathing  is  quite  regular  at  the  time,  and  they 
are  taken  at  the  same  phase  of  the  respiratory  act — 
say  at  the  end  of  inspiration  or  of  expiration.  Ac- 
tually the  percentage  is  varying  distinctly  from 
moment  to  moment  round  the  average;  and  it  is  only 
the  average  that  is  constant.  If,  moreover,  the  per- 
centage of  C02  in  the  air  inspired  is  suddenly 
increased,  it  takes  some  little  time  before  the  breath- 
ing increases  to  the  new  average.  There  is  thus  a 
considerable  lag  between  changes  in  the  alveolar  C02 
percentage  and  the  response  of  the  respiratory  centre. 
This  lag  may  be  in  either  direction.  If,  for  instance, 
the  breathing  is   voluntarily  held   for   a   short  time, 


12        ORGANISM  AND  ENVIRONMENT 

there  follows  excessive  breathing;  and  if  the  alveolar 
air  be  then  analysed  it  will  be  found  that  the  C02 
percentage  has  fallen  below  normal.  The  breathing 
is,  as  it  were,  making  up  for  lost  time. 

This  is  easy  to  understand.  Not  only  does  it  take 
an  appreciable  time  for  the  blood  to  flow  from  the 
lungs  to  the  respiratory  centre,  but  both  the  blood 
and  the  lymph  surrounding  the  tissue  elements  in  the 
respiratory  centre  have  a  large  capacity  for  absorbing 
C02.  They  saturate  and  desaturate  somewhat  slowly 
when  brought  into  connection  with  varying  concen- 
trations of  C02  in  the  alveolar  air.  Consequently  the 
respiratory  centre  only  responds  gradually  to  these 
variations.  Were  it  not  so  the  breathing  would  be 
very  jerky,  and  it  would  be  difficult  to  interrupt  it  in 
speaking  or  singing  or  swallowing.  Momentary  varia- 
tions in  the  alveolar  C02  percentage  have  thus  no 
appreciable  influence  on  the  breathing,  and  it  is  only 
the  average  that  counts.  But  this  average  is  regu- 
lated with  an  accuracy  which  is  extraordinary. 

It  is  evident  that  the  average  percentage  of  C02 
in  the  alveolar  air  can  be  kept  constant  either  by 
shallow  and  frequent  or  by  deep  and  infrequent 
breathing.  We  can  voluntarily  set  the  breathing  to 
very  different  frequencies,  letting  the  depth  take  care 
of  itself.  For  instance  we  can  breathe  three  times  or 
fifty  times  a  minute.  If,  however,  samples  are  taken 
of  the  alveolar  air  when  once  these  different  rates 
have  been  properly  established,  it  is  found  that  the 
average  percentage  of  C02  is  sensibly  the  same. 
Increased  frequency  is  compensated  for  by  diminished 


REGULATION  OF  BREATHING  13 

depth,  and  vice  versa.  It  is  an  entire  mistake  to  judge 
of  the  amount  of  air  breathed  by  the  mere  frequency 
of  the  breathing.  With  very  rapid  and  shallow 
breathing  only  a  little  of  the  pure  inspired  air  clears 
the  air-passages  and  enters  the  lungs.  The  very  rapid 
and  shallow  breathing  of  a  dog  in  hot  weather  does 
not  over-ventilate  its  lungs,  and  is  only  designed  to 
promote  evaporation  from  its  tongue,  and  consequent 
cooling,  since  a  dog  sweats  with  its  tongue,  and  not 
with  its  skin. 

If  the  breathing  is  obstructed,  so  that  considerable 
effort  is  needed  to  draw  in  and  expel  air,  as  in  breath- 
ing through  a  partially  closed  tap,  there  is  still  no 
appreciable  rise  in  the  alveolar  C02  percentage.  The 
breathing  is  less  frequent ;  but  it  is  also  deeper,  and  the 
fundamental  regulation  is  practically  undisturbed. 

It  was  shown  by  Paul  Bert  that  the  physiological 
actions  of  C02  and  various  other  gases  depend  upon 
the  pressure  which  they  exercise.  This  pressure  de- 
pends on  the  number  of  molecules  of  the  gas  present 
in  a  given  volume.  For  instance,  5  per  cent  of  C02 
present  in  dry  air  at  the  normal  sea-level  pressure  of 
760  millimetres  of  mercury  has  a  pressure  of  760  X 
y100  =  38  mm.,  and  exercises  the  same  pressure  as  10 
per  cent  of  C02  in  air  at  380  mm.  barometric  pressure. 
It  also  contains  the  same  number  of  molecules  in  a 
cubic  centimetre.  The  air  in  the  lung  alveoli  is  satu- 
rated with  aqueous  vapour  at  the  body  temperature, 
and  this  vapour  has  a  pressure  of  47  mm.,  which  must 
be  allowed  for  in  calculating  from  an  analysis  the 
pressure  of  C02  in  alveolar  air.    As  already  seen  the 


14        ORGANISM  AND  ENVIRONMENT 

average  percentage  of  C02  in  the  alveolar  air  of  adult 
men  is  5.6.  This  is  calculated  for  dry  air.  Allowing 
for  the  moisture  present  the  pressure  of  C02  with 
normal  barometric  pressure  is  (760 — 47)  X  5,%oo  = 
39.9,  or,  in  round  numbers,  40  mm. 

On  observing  the  alveolar  C02  percentage  at 
increased  or  moderately  diminished  atmospheric  pres- 
sure we  found,  just  as  might  be  expected  from  Paul 
Bert's  experiments,  that  it  is  the  pressure,  and  not 
the  percentage,  of  C02  which  remains  constant.  The 
percentage  is  only  constant  if  the  barometric  pressure 
remains  the  same.  At  five  atmospheres'  pressure  the 
percentage  of  C02  in  moist  alveolar  air  during  rest 
is  only  a  fifth  of  what  it  is  at  normal  pressure.  At 
any  one  position  on  the  earth's  surface  the  changes 
in  barometric  pressure  from  day  to  day  are  so  slight 
that  the  corresponding  changes  in  the  alveolar  C02 
percentage  are  not  very  noticeable;  but  with  con- 
siderable changes  in  altitude,  or  in  the  case  of  workers 
in  compressed  air,  these  changes  may  of  course  be 
very  great. 

We  thus  reach  the  provisional  conclusion  that  the 
breathing  is  so  regulated  as  to  keep  the  pressure  or 
concentration  of  C02  in  the  alveolar  air  constant 
within  narrow  limits.  The  slightest  increase  in  con- 
centration of  C02  causes  an  increase  in  the  breathing 
which  almost  completely  neutralises  the  increase  in 
concentration.  The  slightest  decrease  in  the  con- 
centration of  alveolar  C02  causes  a  compensating 
diminution  in  breathing.  To  put  the  matter  some- 
what  differently,   the   respiratory   centre   reacts   with 


REGULATION  OF  BREATHING  15 

enormous  delicacy  towards  the  slightest  changes,  up- 
wards or  downwards,  in  the  concentration  of  C02  in 
the  alveolar  air  in  contact  with  the  arterial  blood 
which  supplies  the  centre. 

It  is  of  the  highest  significance  that  a  slight  change 
in  the  downwards  direction  is  sufficient  to  suspend 
natural  or  involuntary  breathing.  C02  was  formerly 
regarded  as  merely  a  "waste  product,"  the  getting  rid 
of  which  as  rapidly  and  completely  as  possible  could 
only  be  a  physiological  advantage.  It  has  turned  out, 
however,  that  the  presence  of  a  certain  concentration 
of  C02  is  essential  to  the  continuance  of  breathing. 
This  brings  us  at  once  into  connection  with  a  series 
of  investigations  independently  initiated  by  Professor 
Yandell  Henderson  of  Yale,  and  afterwards  carried 
on  side  by  side  with  the  Oxford  investigations.  His 
work  was  at  first  concerned  mainly  with  the  effects  of 
concentration  of  C02  on  the  circulation,  and  he  found 
that  undue  removal  of  C02  from  the  blood  has  the 
most  disastrous  effects  on  the  circulation,  producing 
symptoms  similar  to  those  observed  in  the  surgical 
condition  known  as  "shock."  He  found  that  when 
C02  is  removed  from  the  body  in  undue  quantity  by 
excessive  artificial  ventilation  of  the  lungs,  the  heart 
and  circulation  gradually  fail,  and  death  results.  To 
this  subject  I  will  return  later;  but  I  am  referring  to 
it  now  in  order  to  emphasise  the  point  that  the  pres- 
ence of  C02  in  a  certain  concentration  in  the  arterial 
blood  is  just  as  necessary  to  life  as,  say,  the  presence 
of  oxygen.  An  environment  of  C02  is  apparently  as 
essential  as  an  environment  of  oxygen. 


16        ORGANISM  AND  ENVIRONMENT 

The  effects  in  man  of  undue  deficiency  or  undue 
excess  of  C02  can  easily  be  observed.  By  forced 
breathing  we  can  greatly  reduce  the  alveolar  C02 
percentage  and  also  the  quantity  of  C02  in  the  arte- 
rial blood.  The  effects  of  continued  forced  breathing 
are  very  marked.  These  are  "swimming"  of  the  head, 
abnormal  sensations  of  "pins  and  needles,"  loss  of 
sensibility,  contractions  of  various  groups  of  muscles, 
and  gradual  loss  of  consciousness.  By  breathing  dur- 
ing rest  air  containing  6  per  cent  or  more  of  C02,  or 
a  less  percentage  during  exertion,  we  can  observe  the 
effects  of  undue  excess  of  C02 — headache,  giddiness, 
and  often  rapid  loss  of  consciousness.  Breathing  is 
so  regulated  as  to  avoid  these  and  other  ill  effects  of 
excess  or  deficiency  of  C02.  In  other  words  the  main- 
tenance of  breathing  is  but  one  manifestation  of  the 
co-ordinated  bodily  activities  of  which  the  outcome  is 
the  maintenance  of  bodily  activity  and  structure  as  a 
whole.  Breathing  is  a  manifestation  of  life  and  there- 
fore possesses  its  characteristic  features. 

It  is  evident  that  the  mechanistic  school  of  physi- 
ologists can  point  to  the  new  facts  with  regard  to  the 
regulation  of  breathing  as  a  confirmation  of  their 
principles.  For  the  respiratory  centre  may  be  re- 
garded as  a  mechanism  which  reacts  in  a  very  sensi- 
tive manner  to  slight  changes  in  the  concentration  of 
C02.  There  is  thus  no  mystery  about  the  regulation 
of  breathing — no  need  to  invoke  the  presence  of 
factors  which  are  not  physical  or  chemical.  The 
respiratory  centre  is,  in  fact,  typical  of  other  bodily 
mechanisms.     The  delicacy  of  their  reaction  is  due 


REGULATION  OF  BREATHING  17 

to  the  delicacy  of  their  mechanism,  and  not  to  the 
interference  of  some  mysterious  guiding  influence 
such  as  the  so-called  "vital  principle." 

But  the  vitalists  can  equally  find  confirmation  in 
the  new  facts.  They  can  lay  stress  on  the  extreme 
delicacy  of  the  regulation,  and  the  fact  that  in  man 
this  delicate  regulation  is  maintained,  day  after  day, 
and  year  after  year,  in  spite  of  all  kinds  of  changes 
in  the  external  environment,  and  in  spite  of  the 
metabolic  changes  constantly  occurring  in  all  living 
tissues.  These  facts  preclude  the  hypothesis  that 
the  respiratory  centre  is  a  permanent  structure  so 
stable  that  it  is  unaffected  by  changes  in  environment. 
The  regulation,  if  it  be  a  mechanism,  is  utterly  mys- 
terious from  the  physical  and  chemical  standpoint, 
and  necessitates  the  assumption  that  a  special  guiding 
influence  is  present,  'such  as  does  not  exist,  so  far  as 
we  know,  in  the  inorganic  world.  The  more  delicate 
and  definite  the  physiological  regulations  which  the 
advance  of  experimental  physiology  is  constantly  dis- 
covering, the  stronger  the  case  for  vitalism. 

I  have  tried  to  put  the  case  fairly  on  both  sides ; 
for  both  sides  have  always  appealed  to  me  strongly, 
and  I  have  been  utterly  unable  to  accept  the  one- 
sided mechanistic  arguments  which  have  been  put  for- 
ward by  many  leading  physiologists  in  recent  times,1 
or  the  equally  onesided  vitalism  of  the  vitalistic 
minority. 

1  As  an  example  of  these  I  may  perhaps  refer  to  Sir 
Edward  Schafer's  Presidential  address  to  the  British  Asso- 
ciation in  1911. 


18        ORGANISM  AND  ENVIRONMENT 

Some  of  the  immediate  practical  applications  of  the 
new  knowledge  with  regard  to  the  regulation  of 
breathing  are  perhaps  of  sufficient  interest  to  be  men- 
tioned shortly.  The  air  of  all  sorts  of  confined  spaces 
is  apt  to  be  vitiated  by  the  presence  of  C02 ;  and  along 
with  the  excess  of  C02  there  is  usually  a  deficiency  of 
oxygen,  since  the  vitiation  is  due  to  processes  of  oxi- 
dation, in  which  oxygen  is  used  up  in  proportion  as 
C02  is  formed.  In  the  air  of  ordinary  rooms  C02 
is  formed  and  oxygen  used  up  by  respiration  and  by 
the  burning  of  illuminants.  The  natural  ventilation 
of  an  ordinary  room  is,  however,  so  considerable  that 
it  is  very  seldom  that  the  percentage  of  C02  in  the 
air  exceeds  0.5  per  cent.  What  effects  will  the  gaseous 
impurity  in  such  air  have?  Clearly  none  that  are 
appreciable.  The  breathing  will  be  very  slightly 
deeper,  so  as  to  keep  the  alveolar  C02  percentage  con- 
stant ;  but  the  increase  in  breathing  will  be  less  than  a 
tenth,  and  such  an  increase  is  totally  unappreciable 
subjectively.  The  slightly  increased  breathing  will 
also  keep  the  oxygen  percentage  in  the  alveolar  air 
from  falling,  so  that  the  diminished  oxygen  percent- 
age in  the  air  will  be  of  no  account.  We  must  thus 
seek  elsewhere  than  in  the  gaseous  impurities  of  the 
air  of  rooms  for  the  causes  of  the  discomfort  felt  in 
crowded  rooms. 

In  mines  and  other  underground  spaces  the  propor- 
tion of  C02  often  goes  much  higher,  and  may  reach 
about  3  per  cent  in  places  where  a  light  will  still  burn. 
With  3  per  cent  of  C02  in  the  air  the  breathing  is 
doubled.     This  effect  becomes  just  noticeable  during 


REGULATION  OF  BREATHING  19 

rest;  but  during  any  exertion  the  effect  is  not  merely- 
noticeable,  but  very  trying.  During  moderate  work 
in  pure  air  the  breathing  is  three  or  four  times  what 
it  is  during  rest;  but  when  air  containing  3  per  cent 
of  C02  is  breathed  the  increase  is  to  6  or  8  times  the 
amount  of  air  breathed  during  rest  in  pure  air.  Pant- 
ing is  thus  very  severe,  and  hinders  all  hard  work. 
Constant  employment  on  hard  work  such  as  mining 
in  air  of  this  composition  is  apt  to  produce  in  the  lungs 
the  condition  known  as  emphysema,  and  thus  to  cause 
premature  disablement.  The  ventilation  of  a  mine 
ought,  therefore,  to  be  at  least  sufficient  to  prevent 
the  C02  percentage  from  exceeding  about  1  per  cent, 
where  no  other  gaseous  impurities  than  C02  are  to 
be  found. 

One  of  the  most  interesting  examples  of  the  effects 
of  CO 2  is  that  which  occurs  in  diving  with  the  ordi- 
nary diver's  equipment.  The  diver  is  supplied  with 
air  by  a  pipe  through  which  air  is  pumped  down  to 
him.  The  air  passes  into  his  helmet,  and  escapes  into 
the  water  by  a  valve  situated  at  the  side  of  the  helmet. 
The  deeper  he  goes  the  greater  is  of  course  the  pres- 
sure at  which  this  air  must  be  supplied ;  and  the  com- 
position of  the  air  which  he  breathes  in  the  helmet 
will  of  course  depend  on  the  amount  of  air  supplied 
to  him  and  on  the  rate  at  which  he  vitiates  this  air. 
During  work,  for  instance,  he  may  produce  four  or 
five  times  as  much  C02  as  during  rest,  so  that  he  will 
need  correspondingly  more  air  during  work. 

Supposing  that  the  diver  is  working  at  a  depth  of 
22  fathoms,  or  132  feet,  the  air  supplied  to  him  will 


20        ORGANISM  AND  ENVIRONMENT 

have  a  total  barometric  pressure  of  five  atmospheres. 
If,  now,  the  rate  of  supply,  as  measured  by  the  strokes 
of  the  pump,  is  such  as  would  keep  the  percentage  of 
C02  in  the  air  of  the  helmet  at  not  more  than  2  per 
cent  during  work,  this  quantity  of  air  would  suffice 
to  keep  him  comfortable  if  he  were  at  or  near  the  sur- 
face. But  if  the  same  quantity  of  air  is  supplied  to 
him  at  22  fathoms,  or  five  atmospheres'  pressure,  the 
effect  of  2  per  cent  of  C02  will,  as  we  have  seen,  be 
the  same  as  that  of  5  X  2  =  10  per  cent  of  C02  at 
surface.  Hence  if  the  diver  exerts  himself  he  will  not 
merely  pant  excessively,  but  rapidly  lose  conscious- 
ness. It  used  to  be  a  common  occurrence  for  divers 
to  lose  consciousness  in  this  way;  and  the  fact  that 
British  naval  divers  were  so  commonly  unable  to  do 
any  work  at  considerable  depths  led  to  an  investiga- 
tion of  the  whole  subject  in  the  light  of  the  new  knowl- 
edge available,  and  to  the  laying  down  of  regulations 
which  now  make  work  quite  easy  at  the  greatest  depths 
required.  The  air  supply  to  a  diver  ought  evidently 
to  be  increased  in  direct  proportion  to  the  increase  in 
the  atmospheric  pressure  at  which  he  works. 

A  diver  is  in  no  danger  from  want  of  oxygen,  since 
the  pressure  of  oxygen  in  his  helmet  and  in  his  alveo- 
lar air  is  always  far  higher  than  in  pure  air  at  surface. 
It  is  almost  always  from  oxygen  want  that  a  man 
dies  who  is  asphyxiated  by  vitiated  air  in  mines ;  but 
a  diver  may  die  from  C02  poisoning  in  the  presence 
of  abundance  of  oxygen. 

I  must  now  turn  to  another  line  of  investigation  in 
relation    to    the    regulation    of    breathing.      In    1868 


REGULATION  OF  BREATHING  21 

Hering  and  Breuer  discovered  that  if  expiration  is 
prevented  by  blocking  the  outlet  of  air  at  the  end  of 
an  inspiration,  particularly  if  the  lungs  are  well  dis- 
tended, rhythmic  breathing  efforts  are  interrupted. 
There  is  a  long  pause,  during  which  there  is  nothing 
but  expiratory  effort;  and  only  after  this  long  pause 
is  there  an  effort  at  inspiration.  Similarly  if  inspira- 
tion is  blocked  at  the  end  of  expiration  there  is  a  long 
interval  in  which  only  inspiratory  effort  is  observed. 
The  rhythmic  activity  of  the  respiratory  centre  is 
interrupted  in  either  case. 

They  also  discovered  that  if  the  vagus  nerves,  which 
proceed  from  the  medulla  oblongata  in  the  brain,  and 
supply  branches  to  the  lungs,  are  cut,  these  effects  are 
no  longer  produced.  Rhythmic  inspiratory  and  expi- 
ratory efforts  continue,  quite  regardless  of  whether 
the  lungs  are  inflated  or  deflated.  Clearly,  therefore, 
impulses  proceeding  up  the  vagus  nerves  from  the 
lungs  are  concerned  in  the  regulation  of  breathing. 
When  these  nerves  are  cut  or  frozen  across  the 
breathing  immediately  becomes  less  frequent,  but 
deeper,  and  acquires  a  well-marked  dragging  char- 
acter. 

Hering  and  Breuer  interpreted  their  observations  as 
signifying  that  with  the  vagus  nerves  intact  disten- 
tion of  the  lungs  excites  the  nerve-endings  with  the 
result  that  impulses  which  stop  or  inhibit  inspiration, 
and  excite  expiration,  pass  up  the  nerves.  On  de- 
flation of  the  lungs  to  a  certain  point  during  expira- 
tion a  corresponding  process  occurs  which  inhibits 
expiration  and  excites  inspiration.     Thus  the  disten- 


22        ORGANISM  AND  ENVIRONMENT 

tion  of  the  lungs  during  inspiration  is  the  immediate 
cause  of  expiration,  and  the  deflation  on  expiration  is 
the  immediate  cause  of  inspiration.  Subsequent  inves- 
tigation by  various  other  observers  confirmed  in  the 
main  these  conclusions.  The  regulation  of  breathing 
thus  appeared  to  be  an  automatic  process  dependent, 
so  long  as  the  vagus  nerves  are  intact,  on  the  effects 
of  alternate  distention  and  deflation  of  the  lungs. 
Until  recently,  also,  many  observers  concluded  from 
their  experiments  that  apnoea  is  the  summed  effect 
of  frequently  repeated  over-distention  of  the  lungs, 
and  has  nothing  to  do  with  chemical  changes  in  the 
blood.  The  majority  believed  that  there  is  both  a 
"chemical"  and  a  "vagus"  apnoea.  The  continued  in- 
spiratory or  expiratory  effort  which  accompanies  con- 
tinuous deflation  or  inflation  of  the  lungs  cannot 
properly  be  called  apnoea,  however. 

I  have  already  referred  to  the  evidence  showing  that 
there  is  certainly  no  such  thing  as  an  apnoea  due  to  the 
mere  summed  effects  of  repeated  distention  of  the 
lungs,  such  as  occurs  in  panting.  The  apnoea  which 
follows  forced  breathing  or  excessive  artificial  ventila- 
tion of  the  lungs  is  due  to  reduction  in  the  amount  of 
C02  in  the  alveolar  air  and  arterial  blood,  and  to  no 
other  cause.  Were  it  the  case  that  repeated  unusual 
distention  of  the  lungs  tends  to  cause  apnoea  we  should 
have  a  physiological  arrangement  exactly  suited  to 
defeat  the  whole  physiological  end  of  increased  breath- 
ing. It  seems  extraordinary  that  the  extreme  improba- 
bility of  this  should  not  have  weighed  more  heavily 
with  the  authors  of  the  "vagus"  theory  of  apnoea. 


REGULATION  OF  BREATHING     23 

The  theory  that  the  breathing  is  regulated  merely 
by  the  effects  of  alternate  distention  and  collapse  of 
the  lungs  is  also  quite  plainly  absurd  in  view  of  what 
is  now  known  about  the  part  played  by  the  carbon 
dioxide  pressure  in  the  alveolar  air  and  arterial  blood. 
The  observations  of  Hering  and  Breuer  and  of  others 
who  have  made  experiments  along  the  same  lines  are 
none  the  less  significant,  however.  Mr.  Mavrogorato 
and  I  have  found  that  the  main  facts,  apart  from  the 
effects  of  section  of  the  vagus  nerves,  can  best  be 
observed  and  analysed  in  man.  The  subject  breathes 
through  a  wide  bored  tap  which  can  be  opened  or 
closed  at  any  moment ;  the  nose  is  clipped ;  and  a  pres- 
sure-gauge is  connected  between  the  mouth  and  the 
tap  so  as  to  show  the  inspiratory  or  expiratory  pres- 
sure. 

When  the  tap  is  closed  at  the  end  of  inspiration  it 
will  be  noticed  on  the  gauge  that  there  is  expiratory 
pressure,  slight  at  first,  but  afterwards  increasing  more 
and  more  rapidly,  till  at  last,  after  an  interval  occupy- 
ing the  time  of  several  normal  respirations,  there  is  a 
sudden  inspiratory  effort.  The  natural  tendency  of  the 
respiratory  centre  to  discharge  alternate  inspiratory 
and  expiratory  impulses  thus  breaks  through  the 
prolonged  expiratory  effort.  Similarly,  if  the  tap  is 
closed  at  the  end  of  inspiration  there  is  a  prolonged 
and  increasing  expiratory  effort.  If,  now,  apnoea 
is  produced  by  forced  breathing  before  the  experiment, 
there  is  inspiratory  or  expiratory  pressure  as  before; 
but  it  is  a  very  long  time  before  this  pressure  begins 
to  increase.    On  the  other  hand  if  air  containing  C02 


24        ORGANISM  AND  ENVIRONMENT 

has  been  breathed  before,  so  that  the  breathing  is 
naturally  increased,  the  inspiratory  or  expiratory  pres- 
sure mounts  up  very  rapidly,  and  is  soon  broken  by 
an  inspiratory  effort.  If  the  tap  is  closed  midway 
in  inspiration,  long-continued  inspiratory  pressure, 
gradually  increasing,  is  shown  on  the  gauge,  just  as 
if  the  interruption  had  been  at  the  end  of  expiration; 
and  similarly  there  is  long-continued  expiratory  pres- 
sure if  expiration  has  been  interrupted  midway. 

If  we  put  together  the  human  observations  and  the 
results  obtained  in  animals  with  the  vagus  nerves 
intact  and  divided,  it  appears  that  the  effect  of  disten- 
tion of  the  lungs  is  to  stop  inspiratory  and  initiate 
expiratory  discharge  of  the  respiratory  centre,  while 
deflation  of  the  lungs  stops  expiratory  and  initiates 
inspiratory  discharge.  Both  inspiratory  and  expira- 
tory discharges  continue  until  they  are  again  stopped 
by  distention  or  deflation.  The  result  is  that  the  dis- 
charges from  the  centre  are  directly  co-ordinated  with 
actual  inflation  or  deflation  of  the  lungs.  This  is 
brought  about  through  the  vagus  nerves.  The  degree 
of  energy  of  the  inspiratory  or  expiratory  discharges 
depends,  however,  on  the  action  of  C02  in  the  blood 
upon  the  centre. 

The  degree  of  inflation  or  deflation  necessary  to 
inhibit  inspiration  or  expiration  and  initiate  expiration 
or  inspiration  depends  quite  clearly  also  on  the  chemi- 
cal stimuli  acting  on  the  centre  through  the  blood : 
for  the  breathing  is  far  deeper  when  the  pressure  of 
COz  in  the  alveolar  air  and  arterial  blood  is  higher. 
We  can  thus  understand  how  it  is  that  when  the  fre- 


REGULATION  OF  BREATHING  25 

quency  of  breathing  is  varied  voluntarily  or  involun- 
tarily, the  depth  naturally  adjusts  itself  in  such  a  way 
that  the  average  alveolar  C02  pressure  remains  sensi- 
bly constant:  for  the  least  lowering  of  alveolar  C02 
pressure  enables  the  Hering-Breuer  inhibitory  effect 
to  become  effective  within  narrower  limits  of  inflation 
and  deflation,  while  the  least  raising  of  alveolar  C02 
pressure  has  the  opposite  effect.  We  can  also  explain 
a  very  interesting  phenomenon  recently  discovered 
independently  by  Yandell  Henderson  in  America  and 
Liljestrand,  Wollin  and  Nilsson  in  Sweden.  When 
artificial  respiration  is  performed  on  a  conscious  sub- 
ject by  Schafer's  or  any  of  the  other  usual  methods, 
air  enters  and  leaves  the  chest  in  just  about  the  normal 
amount,  although  the  subject  carefully  refrains  from 
himself  making  any  breathing  efforts.  If  the  rate 
of  artificial  respiration  is  increased  there  is  no  increase 
in  the  air  entering  the  chest  per  minute :  for  the  breaths 
become  shallower.  If,  finally,  apnoea  is  produced  by 
previous  forced  breathing,  and  artificial  respiration 
is  then  applied,  hardly  any  air  enters  the  chest.  The 
Hering-Breuer  inhibition  comes  into  play  with  the 
slightest  inflation  or  deflation  of  the  lungs,  and  the 
breathing  is,  as  it  were,  jammed. 

When  the  vagi  are  cut,  an  animal  can  still  regulate 
its  breathing  so  as  to  keep  the  alveolar  C02  pressure 
constant ;  for  the  depth  of  the  drawn-out  respirations 
depends  on  the  alveolar  C02  pressure.  But,  as  might 
be  expected,  the  regulation  breaks  down  easily  under 
any  strain,  as  was   recently  shown  by   Scott.     The 


26        ORGANISM  AND  ENVIRONMENT 

breaths  cannot  follow  quickly  enough  the  requirements 
which  are  easily  met  by  an  animal  with  intact  vagi. 

In  the  regulation  of  breathing  we  have  thus  a  strik- 
ing instance  of  the  co-ordination  between  the  actions 
of  two  different  nervous  stimuli.  The  influence  of  the 
peripheral  stimuli  acting  through  the  vagus  nerves  is 
dependent  upon  the  action  of  the  central  stimuli,  and 
vice  versa.  This  interdependence  is  characteristic  of 
the  effects  of  nervous  stimuli  and  indeed  of  all  phys- 
iological stimuli.  As  an  outcome  of  the  interdepend- 
ence in  the  present  case,  the  breathing  organs  work 
as  a  whole,  the  discharges  from  the  respiratory  centre 
being  correlated  with  the  actual  movements  of  the 
lungs. 

Even  after  the  vagi  and  nearly  all  other  nervous 
connections  to  the  respiratory  centre  are  severed,  alter- 
nate inspiratory  and  expiratory  discharges  from  the 
centre  continue  in  their  proper  order.  The  inspiratory 
discharge  seems  during  its  continuance  to  inhibit  ex- 
piratory discharge,  and  vice  versa.  Here,  also,  we  see 
the  co-ordination  which  is  inherent  in  all  physiological 
activity,  and  which  manifests  itself  even  in  the  be- 
haviour of  an  isolated  heart  or  strip  of  muscle,  but  far 
more  strikingly  in  the  case  of  the  nervous  system,  even 
after  great  mutilation,  or  in  the  case  of  the  chemical 
activities  of  any  living  part  of  the  body. 


II 

THE  READJUSTMENTS  OF  REGULATION  IN 
ACCLIMATISATION  AND  DISEASE 

We  have  seen  that  under  ordinary  conditions  the 
regulation  of  breathing  is  dependent  on  very  small 
variations  in  the  degree  to  which  the  arterial  blood 
leaving  the  lungs  is  saturated  with  C02,  and  that  a 
normal  C02  pressure  of  about  40  mm.  is  maintained 
in  the  alveolar  air  of  the  lungs  during  rest.  Never- 
theless this  normal  pressure  may  become  altered.  Thus 
if  the  oxygen  percentage  or  pressure  in  the  lung  air 
becomes  very  low  in  consequence  of  great  deficiency 
in  the  oxygen  percentage  of  the  air  breathed,  or  from 
the  barometric  pressure  being  very  low,  as  at  great 
altitudes,  the  breathing  is  increased  and  the  alveolar 
C02  pressure  falls.  A  similar  fall  occurs  after  mineral 
acids  have  been  taken,  or  in  diseases  in  which  abnor- 
mal quantities  of  acid  are  discharged  into  the  blood, 
or  after  severe  muscular  exertion.  To  understand 
how  the  breathing  is  affected  under  these  various  con- 
ditions, and  on  what  the  normal  conditions  of  breath- 
ing ultimately  depend,  it  is  necessary  to  consider  the 
blood,  and  particularly  the  gases  contained  in  it. 

When  a  liquid  is  brought  into  intimate  contact  with 
a  gas  the  liquid  takes  up  the  gas  in  solution  until  a 
point  is  reached  at  which  equilibrium  or  saturation 
occurs.  At  this  point  as  many  molecules  of  gas  are 
being  given  off  from  the  liquid  as  enter  it,  and  the 


28        ORGANISM  AND  ENVIRONMENT 

pressure  of  the  gas  leaving  the  liquid  is  thus  equal 
to  the  gas  pressure  outside.  If,  as  in  the  lungs,  a 
mixture  of  gases  is  in  contact  with  the  liquid,  the 
pressure  of  each  of  the  gases  in  the  liquid  becomes, 
if  no  interference  to  their  passage  inwards  or  out- 
wards occurs,  equal  to  the  pressure  of  the  correspond- 
ing gas  in  the  gas-mixture.  This  holds  good  even 
if  the  liquid  contains  substances  which  form  well- 
defined  compounds  with  the  gas ;  but  in  the  latter 
case  the  amount  of  gas  which  the  liquid  has  to  take 
up  before  equilibrium  occurs  may  be  very  large.  If  no 
such  chemical  combinations  occur  the  volume  of  gas 
taken  up  by  the  liquid  is  in  ordinary  cases  directly 
proportional  to  the  pressure  of  the  gas. 

As  we  have  already  seen,  the  red  corpuscles  of  the 
blood  contain  a  coloured  albuminous  substance, 
haemoglobin,  which  enters  into  chemical  combination 
with  oxygen.  The  compound,  oxyhaemoglobin,  has 
the  remarkable  property  of  dissociating  freely  as  the 
pressure  of  oxygen  in  the  surrounding  liquid  falls, 
and  re-forming  as  it  rises.  The  oxyhaemoglobin  thus 
acts  as  a  reservoir  of  oxygen,  enabling  the  blood  to 
take  up  or  give  off  far  more  oxygen  with  varying  pres- 
sures of  oxygen  than  water  would  take  up  or  give  off, 
and  thus  to  act  as  a  very  efficient  carrier  of  oxygen 
from  the  lungs,  where  the  oxygen  pressure  is  high,  to 
the  capillary  vessels  of  the  body  tissues,  where  it  is 
low  in  consequence  of  the  constant  consumption  of 
oxygen.  Human  blood  saturated  in  the  lungs  is  capa- 
ble of  giving  off  about  18  cc.  of  oxygen  per  100  cc.  of 
blood,  whereas  water  would  only  give  off  about  0.3  cc. 


READJUSTMENTS  OF  REGULATION     29 

To  understand  the  oxygen  supply  to  the  body,  and  the 
connection  between  oxygen  supply  and  breathing,  it  is 
evidently  necessary  to  understand  the  circumstances 
under  which  oxygen  is  taken  up  or  given  off  by  the 
haemoglobin  of  the  blood.     These  circumstances  can 


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Fig.  1.  Thick  line — dissociation  curve  of  oxyhaemoglobin 
in  blood  in  the  presence  of  40  mm.  pressure  of  CO2. 
Thin  line — the  dissociation  curve  of  oxyhaemoglobin 
in  blood  within  the  body. 


be  investigated  outside  the  body,  provided  that  we 
are  able  to  reproduce  outside  the  body  the  conditions 
which  obtain  within  it.  Until  recently,  failure  to 
appreciate  the  importance  of  this  led  to  great  error. 

The  dissociation  of  oxyhaemoglobin  with  fall  in  the 
pressure  of  oxygen  can  best  be  represented  graphically 
by  a  curve;  and  Figure  1  represents  the  law  of  dis- 


30        ORGANISM  AND  ENVIRONMENT 

sociation  of  human  oxyhaemoglobin  under  the  condi- 
tions so  far  known  to  exist  in  circulating  human  blood, 
including  the  rise  of  C02  pressure  as  the  blood  passes 
the  capillaries.  It  will  be  seen  that  the  curve  has  a 
very  peculiar  shape,  with  a  double  bend,  which  is  of 
great  physiological  significance.  At  the  steep  part  of 
the  curve  oxygen  will  evidently  come  off  freely  with  a 
comparatively  slight  fall  in  oxygen  pressure.  The 
haemoglobin  is  thus  admirably  adapted  for  maintain- 
ing the  oxygen  pressure  approximately  constant  within 
the  pressures  corresponding  to  the  steep  part  as  the 
blood  passes  through  the  capillary  vessels  of  the  body. 
So  far  as  we  know  the  circulation  is  never,  under 
normal  conditions,  so  slow  that  the  oxygen  pressure 
in  the  body  capillaries  falls  below  the  steep  part  of  the 
curve,  and  is  seldom  so  rapid  as  to  bring  the  oxygen 
pressure  above  the  steep  part.  The  oxygen  pressure 
in  the  alveolar  air  is  normally  about  100  mm.,  or  13 
per  cent  of  an  atmosphere,  which  corresponds  to  the 
flat  upper  part  of  the  curve. 

The  general  form  of  the  dissociation  curve  of  the 
oxyhaemoglobin  in  blood  was  discovered  a  few  years 
ago  by  Bohr  of  Copenhagen.  He  and  his  pupils  also 
found  that  the  curve  is  much  affected,  not  only  by 
temperature,  but  by  the  pressure  of  C02  in  the  blood. 
In  the  absence  of  C02  the  curve  (as  represented  in  the 
figure)  shifts  to  the  left,  so  that  oxygen  is  given  off 
much  less  readily.  For  a  specified  amount  of  oxygen 
to  be  given  off  in  the  absence  of  the  C02  normally 
present  in  circulating  blood,  the  pressure  of  oxygen 
would  require  to  be  lowered  to  about  half  the  pressure 


READJUSTMENTS  OF  REGULATION     31 

otherwise  needed.  Excess  of  C02,  on  the  other  hand, 
facilitates  the  dissociation,  so  that  the  giving  off  of 
C02  to  the  blood  in  the  body  capillaries  helps  to  make 
the  curve  steeper  and  so  facilitates  the  oxygen  supply 
to  the  tissues. 

The  curve  is  not  at  all  of  the  shape  which  would  be 
expected  on  purely  chemical  grounds  from  what  is 
known  of  other  substances  which  dissociate  in  a  similar 
manner.  It  was  discovered  by  Barcroft  and  his  pupils 
that  the  inorganic  salts  present  along  with  the  haemo- 
globin in  the  red  corpuscles  determine  this  peculiar 
form.  When  the  haemoglobin  is  freed  from  these 
salts  its  dissociation  curve  has  the  form  which  would 
have  been  expected  on  chemical  grounds — namely,  that 
of  a  rectangular  hyperbola.  With  this  form  of  curve 
the  oxyhaemoglobin  would  be  wholly  unsuited  for 
performing  the  work  which  it  actually  performs  in 
the  body.  The  action  of  the  salts  is  almost  certainly 
connected  with  their  power  of  causing  the  haemoglo- 
bin molecules  to  become  aggregated  into  groups.  Bar- 
croft also  found  that  it  is  in  virtue  of  its  action  as 
an  acid  when  in  solution  that  C02  affects  the  dissocia- 
tion curve.  Alkalies  shift  the  curve  to  the  left,  while 
acids  shift  it  to  the  right;  and  the  changing  position 
of  the  curve  is  an  extraordinarily  delicate  index  of 
small  changes  in  the  reaction  of  the  blood. 

Both  the  plasma  and  the  corpuscles  of  blood  contain 
substances  which  enter  into  chemical  combination  with 
C02;  and  these  combinations  dissociate  with  fall  in 
the  pressure  of  C02,  and  re-form  with  rise,  just  as 
oxyhaemoglobin  dissociates  and  re-forms.    The  whole 


32        ORGANISM  AND  ENVIRONMENT 

of  the  combined  C02  can  be  removed  from  blood  by- 
exposing  it  to  a  vacuum,  just  as  the  whole  of  the  loosely 
combined  oxygen  can  be  removed.  A  strong  acid 
does  not  liberate  any  more.  This  is  a  very  remarkable 
fact;  for  we  cannot  remove  the  C02  from  a  sodium 
carbonate  solution  by  means  of  a  vacuum,  and  sodium 
is  certainly  combined  with  C02  in  blood.  Blood  con- 
tains an  excess  of  alkali  which  is  not  combined  with 
any  strong  acid,  and  must  be  in  part  combined  with 
C02.  The  explanation  lies  in  the  fact  that  haemoglo- 
bin and  other  albuminous  substances  present  in  the 
blood  are  capable  of  acting  as  very  weak  acids  and  so 
partially  preventing  the  C02  from  combining  with  the 
available  alkali.  When  the  pressure  of  C02,  and 
therefore  its  "mass  influence"  is  reduced,  more  and 
more  of  it  is  driven  out  of  combination,  until  with 
the  C02  pressure  at  zero  none  is  left. 

From  100  volumes  of  human  arterial  blood  about 
50  volumes  of  C02  as  gas  are  given  off  to  a  vacuum, 
and  average  venous  blood  contains  only  about  4  vol- 
umes more.  The  relations  between  pressure  of  C02 
and  the  volume  of  C02  absorbed  by  human  blood  were 
recently  investigated  by  Christiansen,  Douglas  and 
myself,  and  Figure  2  represents  the  results  graphically. 
We  found  that  blood  takes  up  considerably  more  C02 
at  a  given  pressure  of  the  gas  when  the  oxyhemoglo- 
bin is  dissociated  than  when  it  is  present  as  oxyhaemo- 
globin.  The  oxyhaemoglobin  thus  acts  as  if  it  were 
a  more  acid  substance  than  dissociated  or  reduced 
haemoglobin.  The  relation  between  pressure  of  C02 
and  its  absorption  by  the  blood  in  the  living  body  is 


READJUSTMENTS  OF  REGULATION     33 


90 


*S"70 


40 


o" 

1 

, 

.*■ 

<s 

-? 

o- 

•^ 

s^» 

> 

'A 

*' 

/'-■ 

/ 

y 

* 

r/ 

V 

*— 

// 

r 

/ 

/ 

11 

1/ 

{ 

30  40  50  60  70  60 


% 


90         100         no        120 


Fig.  2.  Lower  curve — absorption  of  CO2  by  blood  in  pres- 
ence of  air  and  CO2.  Upper  curve — absorption  of  CO2 
by  blood  in  presence  of  hydrogen  and  CO2.  The  line 
A-B  represents  the  absorption  of  CO2  within  the  body. 


therefore  represented  by  the  thick  line  starting  at  40 
mm.  which  is  the  pressure  of  C02  in  arterial  blood. 
This  line  rises  steeply,  so  that  far  more  C02  can  be 
taken  up  by  the  blood  with  a  given  rise  of  C02  pres- 
sure than  would  be  the  case  if  oxyhaemoglobin  and 
reduced  haemoglobin  had  the  same  effect  on  the  ab- 
sorption of  C02.  It  follows  also  that  when  the  venous 
blood  reaches  the  lungs  and  suddenly  becomes  oxy- 
genated, the  pressure  of  C02  in  the  blood  suddenly 
rises.  In  this  way  much  more  C02  is  given  off  than 
would  otherwise  be  the  case  considering  the  existing 


34        ORGANISM  AND  ENVIRONMENT 

pressure  of  40  mm.  in  the  alveolar  air.  In  other  words 
the  oxygenation  of  the  venous  blood  in  the  lungs  helps 
to  turn  out  the  C02 — a  fact  long  ago  suspected  by 
Ludwig,  but  of  which  the  only  evidence  that  could 
be  obtained  was  negative  until  new  and  rapid  methods 
of  blood-gas  analysis  were  introduced  by  Barcroft 
and  myself. 

As  regards  the  carriage  of  both  oxygen  and  C02 
it  is  thus  the  case  that  the  blood  is  of  such  a  nature 
that  the  pressures  of  these  gases  in  the  blood  leaving 
the  tissues  may  vary  but  little  in  spite  of  the  varying 
amounts  of  gas  carried.  With  respect  to  oxygen,  a 
glance  at  the  dissociation  curve  of  oxyhaemoglobin 
shows  that  it  matters  but  little  to  the  saturation  of  the 
blood  with  oxygen  whether  the  oxygen  pressure  in  the 
alveolar  air  is  a  little  higher  or  a  little  lower.  With 
respect  to  C02,  however,  variations  in  the  alveolar 
C02  pressure  will  make  a  distinct  difference  to  the 
C02  pressure  in  the  blood  leaving  the  tissues,  so  that 
it  is  intelligible  that  what  governs  the  breathing  is 
normally  the  C02  pressure,  and  not  the  oxygen  pres- 
sure in  the  arterial  blood. 

A  further  point  about  the  curves  for  both  oxygen 
and  C02  is  that  for  any  one  individual  they  are  ex- 
traordinarily constant  from  day  to  day  and  month  to 
month.  Under  normal  conditions  no  difference  can 
be  detected  in  them,  just  as  with  the  gas  pressures  in 
the  alveolar  air.  The  significance  of  this  constancy 
is  unmistakable;  and  to  a  mechanist  who  pointed  out 
that  the  taking  up  and  giving  off  of  gases  by  the  blood 
is  a  purely  chemical  and  physical  matter,  a  vitalist 


READJUSTMENTS  OF  REGULATION     35 

might  well  retort  by  asking  what  regulates  all  the 
complex  conditions  concerned  in  the  process — the  for- 
mation and  marshalling  of  haemoglobin  and  salts  in 
the  corpuscles,  and  the  astoundingly  delicate  balance  of 
the  various  substances  which  are  concerned  in  the 
carriage  of  C02. 

Nevertheless  the  regulation  of  both  the  breathing 
and  the  carriage  of  gas  by  the  blood  can  be  disturbed, 
either  temporarily  or  for  long  periods ;  and  it  is  only 
by  studying  these  disturbances  that  we  can  get  further 
insight  into  the  regulation.  It  has  already  been  men- 
tioned that  when  mineral  acids  are  administered  the 
breathing  increases,  so  that  the  alveolar  C02  pressure 
necessarily  falls,  while  the  amount  of  C02  in  the 
arterial  blood  may  be  diminished  in  acid  poisoning 
to  a  small  fraction  of  what  it  normally  is.  The 
administration  of  alkalies  has  a  similar  effect  in  the 
opposite  direction.  Slighter  effects  of  a  similar  kind 
can  be  brought  about,  at  least  temporarily,  by  mere 
changes  in  diet.  In  diabetes  a  condition  sometimes 
occurs  in  which  a  great  excess  of  organic  acid  is 
formed  in  the  body;  and  this  also  is  accompanied  by 
great  increase  in  the  breathing  and  fall  in  the  alveolar 
C02  percentage.  A  temporary  effect  in  the  same 
direction  follows  exposure  to  want  of  oxygen,  or 
excessive  muscular  exertion.  It  was  known  that  expo- 
sure to  great  want  of  oxygen  leads  to  the  production 
of  lactic  acid  in  the  body,  and  that  excessive  muscular 
exertion  must  have  the  same  effect,  since  the  amount 
of  work  done  excludes  the  possibility  of  the  circula- 
tion being  able  to  supply  the  muscles  with  the  oxygen 


36        ORGANISM  AND  ENVIRONMENT 

required  to  keep  up  the  work.  These  considerations 
led  me  to  the  conclusion  that  it  is  probably  in  virtue 
of  its  acidity  that  dissolved  C02  (H2COs  or  carbonic 
acid)  affects  the  respiratory  centre,  and  that  other 
acids  will  therefore  have  a  similar  effect,  and  will  thus 
help  C02  to  excite  the  centre.  This  theory  explains 
why  less  C02  in  the  alveolar  air  is  sufficient  to  excite 
breathing  under  the  various  conditions  just  referred 
to. 

At  the  time,  however,  there  was  no  means  available 
of  accurately  measuring  the  slight  alkalinity  of  the 
blood.  The  old  method  of  adding  standard  acid  till 
an  indicator  changed  colour  was  not  only  very  rough, 
but  also  fallacious  in  principle.  The  blood  is  only  very 
slightly  alkaline,  yet  quite  a  large  quantity  of  acid  can 
be  added  to  it  before  it  becomes  acid.  It  is  full  of  so- 
called  "buffer  substances,"  which  are  capable  of  com- 
bining with  acids  or  alkalies,  but  are  not  themselves 
very  definitely  acid  or  alkaline.  Thus  the  amount  of 
acid  which  has  to  be  added  to  blood  to  change  its 
reaction  is  a  measure  of  the  buffer  substances  rather 
than  of  the  alkalinity  of  the  blood.  According  to 
modern  ideas  the  acidity  or  alkalinity  of  a  solution 
depends  on  the  relative  concentrations  in  it  of  hydro- 
gen and  hydroxyl  "ions."  This  concentration  can  be 
measured  directly  by  the  electrometric  method,  but  the 
difficulties  in  applying  the  method  to  blood  were  very 
great. 

In  1912,  however,  Hasselbalch  of  Copenhagen  suc- 
ceeded in  obtaining  reliable  results ;  and  he  and  Lunds- 
gaard  published  curves  showing  graphically  the  rela- 


READJUSTMENTS  OF  REGULATION     37 

tions  between  hydrogen  ion  concentrations  and  COz 
pressure  in  blood.  A  difference  in  C02  pressure  which 
would  be  sufficient  to  double  the  breathing,  or  to  cause 
apnoea,  produced  a  difference  in  hydrogen  ion  concen- 
tration which  was  just  measurable  by  the  method,  so 
the  method  is  very  rough  as  compared  with  the  deli- 
cacy of  discrimination  by  the  respiratory  centre.  By 
varying  the  diet  from  alkaline  to  acid-producing 
Hasselbalch  succeeded  in  producing  a  variation  of 
several  millimetres  in  the  alveolar  C02  pressure.  He 
then  found  that  with  the  blood  saturated  with  C02  at 
the  existing  alveolar  C02  pressure  the  hydrogen  ion 
concentration  as  measured  was  sensibly  the  same  on 
either  diet ;  whereas  if  the  blood  was  saturated  in  both 
cases  at  the  same  C02  pressure  the  hydrogen  ion  con- 
centration was  markedly  different  on  the  two  diets. 
The  difference  in  alveolar  C02  pressure  was  thus  just 
sufficient  to  keep  the  hydrogen  ion  concentration,  in  so 
far  as  it  could  be  measured  by  the  electrometric 
method,  constant  in  the  two  samples  of  blood,  although 
there  was  presumably  a  slight  difference  as  indicated 
by  the  difference  in  the  breathing.  Other  similar  ex- 
periments had  a  similar  result,  and  there  seems  now 
to  be  no  doubt  that  it  is  true  that  what  the  respiratory 
centre  responds  to  is  hydrogen  ion  concentration,  and 
not  mere  C02  pressure. 

The  delicacy  of  the  response  of  the  respiratory 
centre  to  change  in  the  reaction  of  the  blood  is  very 
extraordinary ;  but  what  is  still  more  marvellous  is  the 
fact  that  in  spite  of  this  delicacy  the  alveolar  C02 
pressure  is  so  steady  during  rest.     The  respiratory 


38        ORGANISM  AND  ENVIRONMENT 

centre  is  responsible  for  neutralising,  by  getting  rid 
of  excess  of  C02,  the  changes  in  hydrogen  ion  concen- 
tration which  would  occur  in  the  blood  if  the  excess 
of  C02  were  not  got  rid  of ;  but  its  action  in  regulating 
the  breathing  does  not  explain  why,  apart  from  the 
disturbing  influence  of  CO,,  the  reaction  of  the  blood 
remains  so  marvellously  constant,  as  shown  by  the 
constancy  during  rest  of  the  alveolar  C02  pressure. 
Acid-forming  and  alkali- forming  substances  are  con- 
stantly being  taken  into  the  body  in  more  or  less  irreg- 
ular quantities.  For  instance  the  sulphur  in  albumin- 
ous food  is  oxidised  to  form  sulphuric  acid,  and  the 
phosphorus  to  form  phosphoric  acid;  while  on  the 
other  hand  the  organic  acids  contained  as  salts  in 
vegetable  foods  are  oxidised  to  C02  and  thus  intro- 
duce alkaline  carbonates  into  the  body.  Acid  or 
alkaline  secretions,  such  as  the  gastric  or  pancreatic 
juice,  are  also  being  formed  at  intervals.  Yet  the 
reaction  of  the  blood  hardly  varies  even  when  tested 
by  such  an  exquisitely  sensitive  indicator  as  the  res- 
piratory centre,  while  no  other  indicator  shows  any 
variation. 

It  is  thus  evident  that  to  understand  the  physiology 
of  breathing  we  must  consider  the  regulation  of  the 
blood  alkalinity.  Two  means  are  already  known  by 
which  the  blood-reaction  is  regulated.  One  of  these 
is  by  regulation  of  the  formation  of  ammonia  in  the 
body.  It  was  discovered  by  Schmiedeberg  of  Strass- 
burg  and  his  pupils  that  when  mineral  acids  are  ad- 
ministered to  dogs  or  to  men  the  amount  of  ammonia 
salts  eliminated  in  the  urine  increases  greatly,  at  the 


READJUSTMENTS  OF  REGULATION     39 

expense  of  the  normal  elimination  of  urea.  Urea 
CO(NH2)2  is  a  nitrogenous  body  of  neutral  reactions 
in  the  form  of  which  by  far  the  greater  part  of  the 
combined  nitrogen  passing  through  the  body  is  elimi- 
nated. In  acid  poisoning  the  combined  nitrogen  goes 
more  and  more  into  the  form  of  ammonia  (NH3), 
which,  in  virtue  of  its  alkaline  reaction  when  in  solu- 
tion, combines  with  acids  and  thus  neutralises  them. 
Even  under  average  normal  conditions  in  man  the 
quantity  of  ammonia  eliminated  in  the  urine  is  about 
sufficient  to  neutralise  the  large  quantity  of  sulphuric 
acid  formed  by  the  oxidation  of  the  sulphur  of 
albuminous  substances ;  and  with  an  alkaline  diet  this 
ammonia  practically  disappears  from  the  urine.  In 
the  Strassburg  laboratory  it  was  also  discovered  that 
ammonia  salts  are  converted  into  urea  in  the  liver. 
We  have  now  every  reason  to  believe  that  ammonia 
is  formed  in  large  quantities  in  the  intestine  by  the 
breaking  down  under  ferment  action  of  albuminous 
compounds.  This  ammonia  is  carried  straight  to  the 
liver  by  the  portal  circulation,  and  there  converted 
under  ordinary  conditions  almost  entirely  into  urea. 
But  the  liver  appears  to  leave  unconverted  any  am- 
monia needed  to  regulate  the  reaction  of  the  blood, 
and  the  minutest  deviations  in  reaction  serve  to  regu- 
late this  process.  Hence  in  the  ratio  between  ammonia 
and  total  combined  nitrogen  in  the  urine  we  have  a 
valuable  index  of  any  tendency  towards  acidity  or 
alkalinity  of  the  blood,  though  the  composition  of  the 
alveolar  air  is  a  still  more  direct  index. 

Another  known  means  of  regulation  is  by  the  kid- 


40        ORGANISM  AND  ENVIRONMENT 

neys.  Human  urine  is  usually  acid  in  reaction,  though 
it  is  separated  from  the  alkaline  liquid,  the  blood.  As 
shown  clearly  by  L.  J.  Henderson  of  Harvard,  the 
urine,  like  the  blood,  contains  "buffer"  substances,  so 
that  the  slight  acidity  of  the  urine  is  an  index  of  the 
separation  of  much  acid  from  the  blood.  But  the 
reaction  of  the  urine,  and  therefore  the  separation  of 
acid  by  the  kidneys,  varies  from  hour  to  hour,  and 
depends  on  whether  the  diet  is  more  or  less  acid 
forming  or  alkali  forming.  In  herbivorous  animals, 
which  live  on  an  alkali- forming  diet,  the  reaction  of 
the  urine  is  normally  alkaline;  and  in  man  the  urine 
also  becomes  alkaline  when  alkalies  are  administered. 
It  seems  evident,  therefore,  that  the  kidneys,  as  well  as 
the  liver,  are  constantly  regulating  the  alkalinity  of 
the  blood,  and  doing  so  with  an  accuracy  which  no 
means  of  direct  physical  or  chemical  measurement 
enables  us  to  measure,  but  which  is  shown  by  the  great 
constancy  of  the  alveolar  C02  percentage.  Neverthe- 
less, we  can  be  quite  certain  that  it  is  in  response  to 
the  stimulus  of  very  slightly  altered  reaction  in  the 
blood  that  the  regulating  activity  of  the  liver  and 
kidneys  comes  into  play :  for  by  such  means  as  acid 
poisoning  we  can  make  the  stimulus  so  strong  that 
direct  measurements  can  detect  it. 

It  has  been  rightly  pointed  out  by  L.  J.  Henderson 
that  the  blood,  and  the  body  as  a  whole,  are  so  full  of 
so-called  buffer  substances  that  a  considerable  amount 
of  acid  or  alkali  might  be  added  without  any  measur- 
able disturbance  of  the  blood  alkalinity  being  produced. 
This  is  certainly  true,  and  very  important,  but  the 


READJUSTMENTS  OF  REGULATION     41 

disturbances  which  physiology  has  to  deal  with  are  far 
more  minute  than  those  which  are  appreciable  by 
chemical  methods,  so  that  exact  regulation  of  the 
reaction  of  the  blood  is  indispensable. 

We  have  seen  above  that  the  composition  of  the 
blood  is  so  regulated  that  not  only  is  its  reaction 
practically  constant,  but  the  volume  of  C02  taken  up 
by  a  given  volume  of  blood  at  a  given  pressure  of  C02 
remains  also  the  same  under  ordinary  normal  condi- 
tions. It  is  easy,  however,  to  disturb  this  regulation 
temporarily.  One  means  of  doing  so  is  by  violent 
muscular  exertion.  Douglas  and  I  found  that  a  few 
minutes  after  violent  exertion  the  volume  of  C02 
taken  up  by  a  given  volume  of  human  arterial  blood 
was  reduced  to  about  half.  An  hour  later,  however, 
the  blood  was  again  normal.  The  reduction  was 
probably  due  to  excessive  discharge  of  lactic  acid  into 
the  blood:  for  not  only  was  the  resting  alveolar  C02 
pressure  diminished,  but  Ryffel  succeeded  in  showing 
that  after  similar  violent  exertion  the  proportion  of 
lactic  acid  in  the  blood  and  urine  is  greatly  increased. 
Ryffel  showed  also  that  this  excess  disappears  in  about 
an  hour,  which  is  the  same  time,  as  we  had  observed, 
that  the  alveolar  C02  pressure  requires  to  rise  again  to 
normal  after  a  violent  exertion.  It  is  clear,  however, 
that  the  capacity  of  the  blood  for  taking  up  C02  can- 
not depend  merely  on  its  reaction,  and  must  depend  on 
the  presence  in  regulated  amount  of  all  the  various  sub- 
stances including  albuminous  substances,  which  enter 
into  chemical  reaction  when  C02  is  present.  Their 
amount  must  therefore  be  regulated — probably  by  the 


42        ORGANISM  AND  ENVIRONMENT 

endothelial  cells  which  line  the  capillary  blood-vessels. 
Here,  then,  we  have  another  delicate  regulation  con- 
nected with  breathing. 

We  must  now  turn  to  the  respiratory  regulation  of 
oxygen  supply.  Normally,  as  we  have  seen,  it  is  the 
C02  pressure  in  the  blood,  and  ultimately  the  reaction 
of  the  blood,  which  seems  to  regulate  the  breathing. 
Under  normal  conditions  there  is  always  a  sufficient 
reserve  of  oxygen  in  the  alveolar  air  to  saturate  the 
haemoglobin  of  the  blood  to  about  the  full  normal 
extent,  even  if,  from  any  cause,  the  oxygen  percent- 
age falls  distinctly  below  normal.  We  can  thus  under- 
stand how  it  is  that  even  if  the  oxygen  percentage  in 
the  air  breathed  is  reduced  from  20.9  per  cent,  as  in 
pure  air,  to  as  little  as  14  or  15  per  cent,  which 
instantly  extinguishes  any  ordinary  flame,  the  breath- 
ing is  not  sensibly  affected  at  the  time,  and  the  alveolar 
C02  percentage  is  undisturbed  although  the  alveolar 
oxygen  percentage  has  fallen  from  14  to  7  or  8.  When, 
however,  there  is  a  further  reduction  in  the  oxygen 
percentage  the  breathing  begins  to  increase,  and 
the  alveolar  C02  pressure  consequently  falls.  The 
face  and  lips  also  begin  to  have  a  bluish  or  lead- 
coloured  tinge,  showing  that  the  blood  is  hot  properly 
oxygenated  in  the  lungs ;  and  if  such  air  is  breathed  for 
a  considerable  time  headache  and  nausea  come  on.  If 
there  is  only  6  or  8  per  cent  of  oxygen  in  the  air 
breathed  intense  panting  is  at  once  produced,  accom- 
panied by  rapidly  increasing  dizziness,  mental  fail- 
ure, and  other  alarming  symptoms,  as  well  as  marked 
blueness  or  leaden  colour  of  the  face. 


READJUSTMENTS  OF  REGULATION     43 

On  studying  more  closely  the  effects  of  breathing 
air  very  deficient  in  oxygen  we  found  that  the  alveolar 
C02  pressure  still  regulates  the  breathing ;  but  the 
regulation  is,  as  it  were,  set  at  a  lower  level.  The 
great  panting  produced  at  first  by  want  of  oxygen  is 
due  to  the  fact  that  owing  to  the  large  reserve  of  C02 
in  the  blood  and  lymph  the  alveolar  C02  cannot  be  set 
at  once  to  the  new  level  without  evident  panting. 
When  once  the  reserve  of  C02  has  been  got  rid  of,  the 
breathing  diminishes,  while  the  blueness  and  other 
symptoms  increase.  If  the  oxygen  percentage  or  pres- 
sure in  the  air  is  only  diminished  gradually  there  is  no 
evident  panting,  although  there  is  still  some  increase  in 
the  breathing,  as  shown  by  the  lower  alveolar  C02 
pressure.  The  formidable  symptoms  come  on  without 
the  warning  given  by  panting.  Nevertheless  apnoea 
can  still  be  produced  easily  enough  by  forced  breathing 
sufficient  to  reduce  the  alveolar  C02  pressure  further, 
even  though  the  face  is  blue  all  the  time,  and  con- 
sciousness fails  before  there  is  any  desire  to  breathe. 
It  was  through  attending  too  exclusively  to  want  of 
oxygen  as  a  cause  of  the  "venosity"  of  the  blood  that 
so  many  mistakes  were  made  by  physiologists  as  to 
the  causes  of  apnoea,  and  the  general  physiology  of 
breathing. 

The  action  of  gradually  developing  want  of  oxygen 
is  very  insidious,  until  dangerous  effects  develop  with 
dramatic  suddenness.  These  effects  have  been 
repeatedly  observed  by  balloonists,  as  well  as  in  mines. 
Nothing  illustrates  the  effects  better  than  the  experi- 
ences of  the  well-known  meteorologist  Glaisher  and  his 


44        ORGANISM  AND  ENVIRONMENT 

assistant  Coxwell  in  a  famous  ascent  from  Wolver- 
hampton in  1862.  The  balloon  gradually  reached  a 
height  of  26,000  feet,  at  which  the  oxygen  pressure  in 
the  air  was  reduced  to  two  fifths  of  the  normal. 
Glaisher  then  first  noticed  that  he  could  not  read  his 
instruments  properly.  Shortly  afterwards  his  legs 
were  paralysed,  and  then  his  arms,  though  he  could 
still  move  his  head.  Then  his  sight  failed  entirely,  and 
afterwards  his  hearing,  and  he  became  unconscious. 
Coxwell  meanwhile  endeavoured  to  pull  the  rope  of 
the  valve,  but  found  that  not  only  his  legs,  but  also 
his  arms  were  paralysed.  He  succeeded,  however,  in 
seizing  the  rope  with  his  teeth,  thus  opening  the 
valve.  As  the  balloon  descended  Glaisher,  about  seven 
minutes  after  he  lost  consciousness,  began  to  hear 
Coxwell's  voice  again,  and  then  to  see  him,  after  which 
he  quickly  recovered.  The  balloon  had  probably 
reached  a  height  of  about  30,000  feet. 

In  another  famous  high  ascent  from  Paris  the  three 
observers,  Tissandier,  Sivel  and  Croce-Spinelli,  were 
provided  under  Paul  Bert's  direction  with  bags  of 
oxygen  to  breathe  from  if  they  felt  any  ill  effects. 
Though  the  oxygen  would  have  saved  them  they  were 
all  paralysed  before  they  realised  their  danger;  and 
only  Tissandier  survived.  The  balloon,  as  shown  by 
a  self-registering  barometer,  had  reached  a  barometric 
pressure  of  263  millimetres,  corresponding  to  a  height 
of  30,000  feet,  so  that  the  pressure  was  reduced  to 
nearly  a  third  of  the  normal. 
J  The  insidious  effects  of  want  of  oxygen  are  per- 
haps still  more  strikingly  illustrated  in  the  case  of 


READJUSTMENTS  OF  REGULATION     45 

carbon  monoxide  poisoning.  This  gas  (CO)  is  the 
poisonous  constituent  of  ordinary  lighting  gas;  and 
poisoning  with  it  is  extremely  common  in  America 
on  account  of  the  high  percentage  of  carbon  monoxide 
in  the  carburetted  water  gas  used  extensively  as  a 
substitute  for  the  old-fashioned  coal  gas  still  supplied 
in  England.  I  discovered  about  twenty  years  ago  that 
CO  poisoning  is  also  the  cause  of  nearly  all  the  deaths 
in  great  colliery  explosions  and  fires,  and  a  source  of 
extreme  danger  to  rescuers. 

Claude  Bernard  found  that  CO  enters  into  combina- 
tion with  haemoglobin,  just  as  oxygen  does,  but  forms 
a  far  more  stable  compound.  In  presence,  therefore, 
of  sufficient  CO  the  oxygen-carrying  power  of  the 
haemoglobin  is  suspended,  and  death  must  result  from 
want  of  oxygen.  It  was  supposed  that  CO  has  also  a 
direct  poisonous  action  on  the  nervous  system.  That 
this  is  not  so  I  succeeded  in  showing  by  placing  ani- 
mals in  compressed  oxygen  before  giving  them  CO. 
In  the  compressed  oxygen  sufficient  oxygen  goes  into 
ordinary  physical  solution  in  the  blood  to  enable 
the  animal  to  dispense  with  oxyhaemoglobin  as  an 
oxygen  carrier;  and  the  animal  remains  unharmed 
although  its  blood  and  tissues  are  saturated  with  CO. 
Animals  which  do  not  employ  oxygen  haemoglobin  as 
an  oxygen  carrier  live  for  weeks  quite  comfortably  in 
an  artificial  air  composed  of  80  per  cent  of  CO  and 
20  per  cent  of  oxygen.  CO  is  not  oxidised  in  the 
living  body,  and  apart  from  its  one  fatal  property  of 
combining  with  haemoglobin  it  is  a  physiologically 
indifferent  gas. 


46        ORGANISM  AND  ENVIRONMENT 

In  CO  poisoning  there  is  usually  only  a  small  per- 
centage of  CO  in  the  air,  and  as  the  haemoglobin  of 
the  blood  has  a  large  capacity  for  CO  it  takes  a  con- 
siderable time  for  enough  CO  to  accumulate  in  the 
blood  to  cause  dangerous  symptoms.  These  symp- 
toms, however,  come  on  in  exactly  the  same  insidious 
manner  as  those  from  oxygen  want  arising  in  any 
other  way.  The  headache,  nausea,  etc.,  of  CO  poison- 
ing are  the  same  as  those  of  mountain  sickness,  and 
the  more  remote  nervous,  cardiac,  and  other  after- 
symptoms  of  CO  poisoning  or  serious  oxygen  want 
produced  in  any  other  way  are  due  to  damage  result- 
ing from  oxygen  want,  and  to  no  other  cause.  The 
oxygen  want  produces  not  merely  temporary  func- 
tional effects,  but  structural  changes  in  the  cells  of 
nervous  and  other  tissues. 

As  CO  in  small  but  extremely  dangerous  propor- 
tions in  air  cannot  be  detected  by  smell  or  by  a  lamp, 
I  introduced,  as  a  test  for  it,  the  use  of  a  small  warm- 
blooded animal,  such  as  a  mouse  or  canary.  A  small 
animal  has  an  enormously  greater  respiratory  ex- 
change and  circulation  rate  than  a  man ;  and  in  con- 
sequence its  blood  becomes  saturated  with  CO  far 
more  quickly.  By  watching  the  animal  a  miner  can 
tell  in  good  time  whether  he  is  in  a  dangerous  atmos- 
phere, though  in  the  long  run  the  animal  is  not  more 
sensitive  to  CO  than  the  man.  The  provision  of  small 
animals  for  testing  purposes  at  mines  in  Great  Britain 
was  made  obligatory  by  recent  legislation. 

Yandell  Henderson  discovered  that  after  excessive 
artificial   respiration   on   animals   the   breathing   does 


READJUSTMENTS  OF  REGULATION     47 

not  return.  The  animal  dies  of  want  of  oxygen,  or 
failure  of  the  circulation,  without  making  any  effort 
to  breathe.  Hence  if  we  reduce  the  C02  pressure 
of  the  blood  low  enough  no  amount  of  oxygen  want 
will  excite  the  respiratory  centre.  Oxygen  want  is 
thus  not  by  itself  an  adequate  stimulus  to  the  respira- 
tory centre ;  but  it  helps  the  action  of  C02,  or  if  we 
like  to  put  it  otherwise,  causes  the  respiratory  centre 
to  react  in  presence  of  a  degree  of  blood  alkalinity 
which  would  be  too  high  to  excite  it  under  normal 
conditions. 

Although  a  slight,  or  even  a  considerable,  deficiency 
in  the  oxygen  pressure  of  the  air  breathed  produces 
no  immediate  effect  on  the  breathing,  yet  a  long-con- 
tinued deficiency  has  a  very  distinct  effect;  and  the 
study  of  the  effects  of  a  long-continued  deficiency  has 
furnished,  I  think,  one  of  the  most  interesting  chap- 
ters in  recent  physiology.  To  observe  the  effects  of 
long-continued  deficiency  it  is  only  necessary  to  go 
to  places  at  high  altitudes,  where  the  barometric  pres- 
sure is  low,  but  where  men  nevertheless  live  under 
perfectly  healthy  conditions.  The  Anglo-American 
expedition  to  Pike's  Peak  in  1911  had  for  its  object 
the  careful  study  of  these  effects. 

On  going  to  a  very  high  altitude  the  breathing  is 
increased  at  once,  and  the  alveolar  C02  pressure  falls 
correspondingly ;  but  if  the  altitude  is  only  very  mod- 
erate there  is  at  first  no  effect  on  the  breathing,  just 
as  happens  when  air  containing  a  moderately  reduced 
percentage  of  oxygen  is  breathed  in  the  laboratory 
for  a  short  time.     After  some  days,  however,  it  will 


48        ORGANISM  AND  ENVIRONMENT 

be  found  that  the  alveolar  C02  pressure  has  fallen, 
which  shows  that  the  breathing  is  deeper.  This  fall 
reaches  a  certain  amount,  depending  on  the  altitude, 
and  then  ceases.  On  the  subject's  return  to  sea  level 
the  alveolar  C02  pressure  does  not  at  once  return  to 
normal  again,  but  may  take  many  days,  or  even  some 
weeks,  to  do  so.    Figure  3  shows  graphically  the  aver- 


*w«  Pr,t,.S0O     750      TOO     650     600     330     000     W      *00     3S0     300     £30    £00 
*—**?  ||  |  III  III  I 

/IHHvJi  in  H.         0      2000    4000    6000  8000   10000  14000   16000  20000    26000 

Fig.  3.  Alveolar  pressures  of  oxygen  and  CO2  and  per- 
centages of  haemoglobin  in  the  blood  of  persons  ac- 
climatised to  altitudes  from  sea  level  to  14,000  feet, — 
barometric  pressures  from  760  to  450  mm.  of  mercury. 


READJUSTMENTS  OF  REGULATION     49 

age  results  of  measurements  of  alveolar  C02  pressure 
made  by  Miss  Fitz  Gerald,  in  connection  with  the 
Pike's  Peak  Expedition,  on  persons  residing  perma- 
nently at  different  altitudes.  It  will  be  seen  that  the 
alveolar  C02  pressure  diminishes  regularly  with  alti- 
tude, starting  from  sea  level.  That  this  diminution 
is  a  response  to  the  diminished  alveolar  oxygen  pres- 
sure there  can  be  no  doubt.  If  the  barometric  pres- 
sure is  kept  steady,  and  the  oxygen  pressure  is  dimin- 
ished by  lowering  the  percentage  of  oxygen,  the  re- 
sults are  precisely  the  same,  so  far  as  can  be  judged  by 
the  available  observations;  and,  as  was  first  clearly 
pointed  out  by  Paul  Bert,  practically  all  the  physiologi- 
cal disturbances  produced  by  low  barometric  pressures, 
or  high  altitudes,  are  due  to  lowering  of  the  oxygen 
pressure. 

From  Figure  3  it  is  pretty  evident  that  if  the  oxygen 
pressure  is  raised  above  the  normal  value  at  sea  level, 
the  alveolar  COz  pressure  will  rise  still  higher.  That 
this  is  actually  the  case  has  recently  been  shown  by 
Hasselbalch  and  Lindhard,  who  have  confirmed  in  a 
steel  chamber  many  of  the  Pike's  Peak  results,  and 
have  added  further  observations  of  their  own.  It 
appears  from  their  results  that  the  alveolar  C02 
pressure  does  not  rise  much  higher  after  the  normal 
oxygen  alveolar  oxygen  percentage  has  been  exceeded ; 
but  the  fact  that  there  is  a  rise  is  of  great  interest,  as 
showing  that  even  the  "normal"  alveolar  C02  pressure 
depends  on  the  existing  alveolar  oxygen  pressure. 

What  is  the  significance  of  the  fall  in  alveolar  C02 
pressure  at  low  barometric  pressures?     It  might  be 


50        ORGANISM  AND  ENVIRONMENT 

thought  that  the  teleological  significance  at  any  rate  is 
clear  enough,  since  lowering  of  alveolar  C02  pres- 
sure means  raising  of  the  oxygen  pressure,  thus  com- 
pensating to  some  extent  for  any  want  of  oxygen 
caused  by  the  lowered  oxygen  pressure.  But  there 
may  be  no  evident  signs  of  want  of  oxygen,  and  lower- 
ing of  alveolar  C02  pressure  is  in  itself  a  very  dis- 
turbing influence,  as  has  already  been  shown.  When 
we  first  observed  the  persistent  lowering  of  alveolar 
C02  pressure  in  connection  with  shorter  experiments 
in  a  steel  chamber  we  thought  that  lactic  acid  must 
have  been  formed  in  consequence  of  oxygen  want,  and 
that  the  persistence  of  the  lowered  alveolar  C02 
pressure  after  the  experiment  was  due  to  lactic  acid 
remaining  in  the  body.  But  further  observations  by 
Boycott  and  RyfTel  failed  to  confirm  this  theory;  and 
the  persistence  observed  after  longer  observations  in 
the  chamber,  and  stays  in  the  Alps,  was  far  too  great 
to  justify  the  lactic  acid  theory.  As  already  men- 
tioned the  excess  of  lactic  acid  produced  by  muscular 
work  disappears  from  the  blood  within  about  an  hour. 
Barcroft  meanwhile  found  on  the  Peak  of  Tenerifle 
that  the  dissociation  curve  of  the  oxy haemoglobin  in 
human  blood  was  displaced  to  the  right  if  the  deter- 
mination is  made  in  presence  of  40  mm.  pressure  of 
C02  (that  of  the  alveolar  air  at  sea  level),  but  was 
normal  if  made  in  presence  of  the  existing  lowered 
alveolar  C02  pressure.  From  this  it  could  be  con- 
cluded that  there  is  no  appreciable  change  in  the 
reaction  of  the  arterial  blood  within  the  body  at  the 
higher  altitude.     The  lowered  alveolar  C02  pressure 


READJUSTMENTS  OF  REGULATION     51 

just  compensated  sensibly  for  diminished  alkalinity 
of  the  blood.  This  we  confirmed  on  Pike's  Peak  at  a 
higher  altitude. 

As  a  result  of  the  whole  of  the  Pike's  Peak  and 
previous  experiments  we  came  to  the  conclusion  that 
the  point  of  alkalinity  to  which  the  kidneys,  etc.,  regu- 
late the  blood  is  altered  in  the  direction  of  slightly 
diminished  alkalinity,  so  that,  assuming  the  reaction 
of  the  respiratory  centre  to  alkalinity  to  be  steady,  the 
alveolar  C02  pressure  has  to  be  kept  lower  in  order 
to  preserve  the  balance.  The  very  slight  diminution 
of  alkalinity  required  to  account  for  the  increased 
breathing  is  so  small  as  to  be  at  present  beyond  the 
range  of  measurement,  as  already  explained.  Hassel- 
balch  and  Lindhard  have  more  recently  published  the 
results  of  electrometric  measurements  of  the  arterial 
blood  alkalinity  which  show  a  sensibly  unaltered 
reaction  after  acclimatisation  to  lowered  barometric 
pressure  in  a  steel  chamber,  with  the  alveolar  C02 
pressure  much  reduced. 

It  thus  appears  that  the  regulation  of  the  alkalinity 
of  the  blood  by  the  kidneys  and  liver  is  dependent  on 
the  oxygen  pressure  of  the  air.  The  change  in  envi- 
ronment has  altered  the  setting  of  the  regulator.  This 
is  a  very  striking  example  of  the  intimate  connection 
between  internal  physiological  regulation  and  external 
environment;  but  we  have  now  to  consider  other 
instances. 

It  has  long  been  known  that  the  percentage  of 
haemoglobin  and  relative  number  of  red  corpuscles 
increases  at  high  altitudes.     Figure  3  represents  the 


52        ORGANISM  AND  ENVIRONMENT 

results  of  Miss  Fitz  Gerald's  observations  on  the 
haemoglobin  percentages  in  persons  permanently  living 
at  different  altitudes.  These  observations  were  all 
made  by  the  colorimetric  method  of  determination 
which  I  introduced  a  few  years  ago,  and  with  a  care- 
fully standardised  instrument.  It  will  be  seen  that 
just  as  the  alveolar  C02  rises  with  fall  in  the  baro- 
metric pressure,  so  the  haemoglobin  percentage  rises. 
It  appears  also  that  in  an  atmosphere  with  a  higher 
oxygen  pressure  than  air  at  sea  level  a  decrease  in  the 
haemoglobin  percentage  below  what  is  termed  "nor- 
mal" would  occur.  Here  also,  then,  the  setting  of  the 
regulation  of  haemoglobin  percentage  is  altered  by 
change  in  environment. 

Using  the  carbon  monoxide  method  of  Lor  rain 
Smith  and  myself,  we  found  that  on  going  to  a  high 
altitude  not  only  the  percentage  amount,  but  also  the 
total  amount  of  haemoglobin  in  the  blood  is  increased. 
The  total  volume  of  the  blood  seems  to  diminish 
at  first,  thus  raising  the  concentration  of  haemo- 
globin; but  after  a  few  days  the  volume  of  the  blood 
increases  above  normal.  The  regulation  of  total 
haemoglobin,  concentration  of  haemoglobin,  and  blood 
volume  are  thus  all  dependent  on  the  oxygen  pressure 
of  the  air  breathed. 

I  now  come  to  what  was  the  most  striking  result  of 
the  expedition.  In  the  lungs  the  blood  is  separated 
from  the  alveolar  air  by  an  extremely  thin  membrane 
consisting  of  the  "protoplasm"  of  flattened  epithelial 
cells.  Do  these  cells  play  any  active  part  in  the  gaseous 
exchange  between  the  air  and  the  blood?     Or  does 


READJUSTMENTS  OF  REGULATION     53 

the  gas  simply  pass  through  them  by  ordinary  diffu- 
sion? This  question  has  been  debated  ever  since  a 
suggestion  that  they  may  play  some  active  part  was 
made  by  Ludwig  forty  or  fifty  years  ago. 

By  means  of  an  apparatus  known  as  the  aeroto- 
nometer,  Pfliiger  and  his  pupils  compared  the  pressure 
of  C02  in  the  blood  with  that  in  alveolar  air,  and 
found  it  to  be  about  the  same.  The  aerotonom- 
eter  was  then  improved  by  Bohr  of  Copenhagen, 
an  old  pupil  of  Ludwig.  His  results  seemed  to  show 
that  sometimes  there  is  a  lower  pressure  of  C02,  and 
a  higher  pressure  of  oxygen  in  the  arterial  blood  than 
in  the  lung  air,  in  which  case  an  active  secretion  of 
oxygen  inwards,  and  of  C02  outwards,  must  be 
assumed.  Fredericq  then  got  results  in  favour  of  the 
simple  diffusion  theory.  Last  of  all  Krogh  of  Copen- 
hagen improved  the  aerotonometer  still  further,  and 
obtained  results  which  again  favoured  the  diffusion 
theory. 

Meanwhile  Lorrain  Smith  and  I  attacked  the  prob- 
lem by  a  new  method,  which  was  suggested  to  me  by 
the  study  of  CO  poisoning,  and  which  eliminated  cer- 
tain sources  of  very  serious  error  in  the  aerotonometer 
method  of  measuring  the  arterial  oxygen  pressure. 
When  blood  is  saturated  with  a  mixture  containing 
both  oxygen  and  CO  the  haemoglobin  combines  partly 
with  CO  and  partly  with  oxygen  in  perfectly  definite 
proportions  depending  on  the  relative  pressures  of 
the  two  gases,  although  in  consequence  of  the  far 
greater  affinity  of  CO  for  haemoglobin  the  pressure 
of  oxygen  must  be  about  300  times  greater  than  the 


54        ORGANISM  AND  ENVIRONMENT 

pressure  of  CO  if  the  haemoglobin  of  human  blood 
at  body  temperature  is  to  be  divided  equally  between 
the  two  gases.  Clearly,  therefore,  if  the  pressure  of 
CO  is  known,  and  also  the  percentage  saturation  of 
the  blood  after  equilibrium  has  occurred,  the  pressure 
of  oxygen  can  be  calculated  very  exactly.  We  there- 
fore breathed  an  exactly  known  small  percentage  of 
CO  until  the  blood  ceased  to  take  up  any  more  CO. 
We  then  determined  the  percentage  saturation  of  the 
haemoglobin  with  CO,  and  the  pressure  of  CO  in  the 
alveolar  air.  From  these  data  we  calculated  the  pres- 
sure of  oxygen  in  the  blood  leaving  the  lungs.  CO,  as 
already  mentioned,  is,  apart  from  its  action  on  haemo- 
globin, a  physiologically  indifferent  gas  like  nitrogen  or 
hydrogen.  It  is  not  oxidised  in  the  body,  and  it 
appears  to  pass  freely  by  simple  diffusion,  like  nitro- 
gen or  hydrogen.  We  could  therefore  assume  that  it 
diffuses  freely  into  the  blood  and  finally  reaches  a 
pressure  which  is  the  same  in  the  blood  of  the  lungs 
as  in  the  alveolar  air. 

In  the  human  experiments  we  reached  the  appar- 
ently unmistakable  result  that  the  oxygen  pressure  in 
the  blood  leaving  the  lungs  is  considerably  higher  than 
in  the  alveolar  air,  and  that  there  is  therefore  active 
secretion  inwards.  Experiments  with  animals  showed, 
further,  that  when  the  percentage  of  CO  was  in- 
creased so  as  to  produce  symptoms  of  oxygen  want 
the  evidence  of  active  secretion  became  much  more 
striking. 

On  repeating  the  human  experiments  at  a  later  date 
we  could  not  get  the  same  results.    Douglas  and  I  then 


READJUSTMENTS  OF  REGULATION     55 

improved  the  method  further,  and  found  that  both 
in  animals  and  in  ourselves  we  got  results  wholly  con- 
sistent with  the  diffusion  theory,  provided  that  the 
percentage  of  CO  was  kept  very  low.  If  sufficient 
CO  was  given  to  produce  symptoms  of  oxygen  want 
we  got  active  secretion.  We  also  got  active  secretion 
if  oxygen  want  was  produced  in  a  group  of  muscles 
by  fatiguing  work.  Nevertheless  the  human  experi- 
ments gave  on  the  whole  a  much  less  striking  result 
than  the  former  ones,  and  we  could  not  at  the  time 
see  any  reason  for  this. 

The  apparent  acclimatisation  to  oxygen  want  in 
mountaineers  or  persons  living  at  high  altitudes  then 
attracted  our  attention,  and  in  conjunction  with  Yan- 
dell  Henderson  the  Pike's  Peak  Expedition  (in  which 
he,  Douglas,  Schneider  and  I  participated,  while  Miss 
Fitz  Gerald  made  observations  at  neighboring  mining 
camps  and  towns)  was  planned.  When  we  reached 
the  summit  of  Pike's  Peak  (14,100  feet)  we  were  all 
more  or  less  blue  in  the  lips,  as  were  other  newcomers. 
We  then  suffered  in  various  degrees  for  two  or  three 
days  from  mountain  sickness,  after  which  the  blueness 
entirely  disappeared,  although  our  alveolar  oxygen 
pressures  remained  nearly  the  same  as  while  the  blue- 
ness was  present,  and  our  haemoglobin  percentages 
had  not  as  yet  risen  appreciably.  After  this  we  made  a 
number  of  determinations  of  the  arterial  oxygen  pres- 
sure, and  each  one  without  exception  showed  a  consid- 
erably higher  pressure  of  oxygen  in  the  arterial  blood 
than  in  the  alveolar  air.  On  the  other  hand,  when  we 
breathed  during  the  experiment  air  rich  in  oxygen,  so 


56        ORGANISM  AND  ENVIRONMENT 

as  to  bring  the  alveolar  oxygen  to  about  the  normal  at 
sea  level,  the  difference  between  arterial  and  alveolar 
oxygen  pressure  almost  disappeared.  We  then  deter- 
mined the  arterial  oxygen  pressure  in  a  newcomer  who 
was  still  blue,  but  did  not  become  mountain-sick  till 
some  hours  later.  It  was  very  little  above  the  alveolar 
oxygen  pressure;  but  three  days  later  when  he  was 
acclimatised  and  well,  his  arterial  oxygen  pressure  was 
as  high  as  our  own.  The  mean  result  was  that  on 
Pike's  Peak,  after  acclimatisation,  the  arterial  oxygen 
pressure  was  during  rest  only  about  13  mm.  lower  than 
at  sea  level,  but  was  35  mm.  higher  than  the  alveolar 
oxygen  pressure.  The  complete  absence  of  any  blue- 
ness  after  acclimatisation  was  thus  easily  intelligible. 
The  lungs  were  actively  secreting  oxygen  into  the 
blood,  even  during  rest.  Nevertheless  the  blueness 
reappeared  temporarily  during  prolonged  muscular 
exertions,  as  in  a  long  climb.  The  lung  epithelium 
could  thus  apparently  be  fatigued  by  the  extra  work 
thrown  upon  it. 

As  already  seen,  the  lung  epithelium  is  at  all  times 
capable  of  actively  secreting  oxygen  inwards  if  the 
requisite  stimulus  arising  from  oxygen  want  in  the 
tissues  is  present.  But  at  high  altitudes  this  capacity 
is  greatly  increased,  and  secretion  goes  on  continuously 
after  acclimatisation.  The  stimulus,  moreover,  is 
essentially  the  same  stimulus  as  produces  the  changes 
in  the  regulation  of  blood  alkalinity  and  in  the  haemo- 
globin of  the  blood.  The  stimulus  is  want  of  oxygen 
in  some  form ;  but  how  does  the  want  of  oxygen  act  ? 
The  haemoglobin  of  the  arterial  blood  must,   after 


READJUSTMENTS  OF  REGULATION     57 

acclimatisation,  be  practically  as  fully  saturated  as 
usual ;  and  considering  the  increase  in  the  haemoglobin 
percentage  the  amount  of  oxygen  in  the  arterial  blood 
must  be  greater  than  normal.  The  oxygen  consump- 
tion during  rest  was  the  same  on  Pike's  Peak  as  at 
sea  level,  and  the  circulation  rate,  so  far  as  our  tests 
could  determine  it,  was  about  the  same.1  Hence  the 
oxygen  pressure  in  the  capillaries  of  the  body  would 
be  somewhat  higher  than  usual,  and  our  unusually 
rosy  color  seemed  to  confirm  this. 

The  most  probable  explanation  as  to  how  oxygen 
want  produces  these  effects  is  that  there  is  some  sub- 
stance which  normally  undergoes  almost  complete  oxi- 
dation in  the  lungs  at  each  round  of  the  circulation. 
At  high  altitudes  it  escapes  past  the  lungs  in  abnormal 
quantity  in  consequence  of  the  lowered  oxygen  pres- 
sure, and  probably  also  of  the  longer  time  required  by 
the  blood  in  the  lungs  to  reach  its  full  oxygen  pres- 
sure. There  are  many  facts  pointing  to  the  assump- 
tion that  such  a  substance  exists  and  that  its  presence 
in  the  blood  is  the  source  of  various  phenomena  accom- 
panying oxygen  want. 

The  increase  in  the  capacity  of  the  lung  epithelium 
to  secrete  oxygen  is  comparable  to  the  increased 
efficiency  produced  in  almost  any  organ  by  increased 
use.  This  increased  capacity  suggests  the  probable 
explanation  of  why  in  the  original  human  experiments 
of  Lorrain  Smith  and  myself  we  obtained  much  more 

1  By  more  accurate  tests  Krogh  and  Lindhard  have  re- 
cently shown  definitely  that  there  is  no  alteration  in  the 
circulation  rate  after  acclimatisation  in  a  steel  chamber. 


58        ORGANISM  AND  ENVIRONMENT 

striking  results  than  in  the  later  experiments  of  Doug- 
las and  myself.  The  earlier  experiments  were  very- 
long  ones,  and  we  were  frequently  exposing  ourselves 
to  oxygen  want  for  many  hours  at  a  time.  We  had 
probably  thus  both  become  more  or  less  acclimatised, 
so  that  our  lung  epithelium  reacted  very  promptly  to 
the  slight  oxygen  want  produced  by  the  CO.  In  no 
other  way  can  I  explain  the  fact  that  we  were  able  to 
breathe  with  complete  impunity  percentages  of  carbon 
monoxide  which  in  subsequent  isolated  experiments 
were  found  to  produce  severe  symptoms.  The  same 
criticism  applies  to  my  own  early  experiments  as  to 
the  effects  of  definite  percentages  of  CO.  I  was 
breathing  CO  every  day  often  for  hours,  and  doubt- 
less had  become  highly  acclimatised  to  want  of  oxy- 
gen, so  that  I  underestimated  the  effects  of  CO  on 
ordinary  unacclimatised  persons. 

The  part  played  by  the  lung  epithelium  in  acclimati- 
sation to  want  of  oxygen  makes  it  possible  to  under- 
stand how  mountaineers  have  succeeded  in  reaching 
such  great  heights  as  they  have.  In  his  recent  explora- 
tions in  the  Himalayas  the  Duke  of  the  Abruzzi 
reached  the  height  of  24,600  feet,  the  barometric  pres- 
sure being  only  312  mm.  An  unacclimatised  person  at 
this  pressure  is  rapidly  disabled  completely;  but  the 
Duke's  party  did  not  suffer  at  all  from  mountain  sick- 
ness or  other  serious  physiological  inconvenience. 
Dr.  Filippi,  a  member  of  the  expedition,  in  his  account 
of  it  expresses  the  opinion  that  there  is  no  such  thing 
as  mountain  sickness  due  to  rarefaction  of  the  air.  He 
was  entirely  deceived  by  the  influence  of  acclimatisa- 


READJUSTMENTS  OF  REGULATION     59 

tion,  just  as  I  was  in  the  case  of  CO  poisoning.  On 
rereading  Glaisher's  account  of  his  balloon  expe- 
riences I  was  much  interested  to  see  that  though  he  did 
not  clearly  understand  the  cause  of  mountain  sickness 
he  was  quite  convinced  that  repeated  ascents  produced 
acclimatisation.  I  have  recently  found  that  the  effects 
of  acclimatisation  can  easily  be  observed  at  ordinary 
atmospheric  pressure  in  a  closed  chamber  in  which  the 
oxygen  percentage  has  been  greatly  reduced.  An 
acclimatised  person  remains  of  a  normal  colour,  and 
has  no  unpleasant  symptoms,  while  an  unacclimatised 
person  soon  becomes  blue  in  the  face,  and  may  faint. 

In  acclimatisation  to  high  altitudes  there  are  evi- 
dently three  factors — the  increased  activity  of  the 
lung  epithelium  in  absorbing  oxygen,  the  increased 
breathing,  and  the  increased  percentage  of  haemo- 
globin. Of  these  the  last  raises  the  oxygen  pressure 
in  the  capillaries  of  the  body,  the  second  diminishes 
the  fall  in  alveolar  oxygen  pressure,  and  the  first 
raises  the  arterial  oxygen  pressure  much  above  the 
alveolar  oxygen  pressure,  whereas  at  sea  level  the 
arterial  oxygen  pressure  is  no  higher,  as  a  rule,  than 
the  alveolar  oxygen  pressure.  The  teleological  sig- 
nificance of  these  changes  seems  clear,  and  a  vitalist 
would  naturally  point  to  this  as  evidence  of  the  inter- 
ference of  the  vital  principle.  But  we  must  analyse 
the  facts  further. 


Ill 

REGULATION  OF  THE  ENVIRONMENT. 
INTERNAL  AND  EXTERNAL 

We  must  now  attempt  to  analyse  the  meaning  of 
the  fact  that  the  pressure  of  oxygen  may  be,  and  at 
high  altitudes  always  is,  higher  in  the  arterial  blood 
than  in  the  alveolar  air.  The  layer  separating  the 
blood  from  the  alveolar  air  in  the  lungs  appears  under 
the  microscope  as  an  extremely  thin  layer  of  moist 
albuminous  material  made  up  of  flattened  cells.  In 
such  a  layer  gases  are  soluble,  just  as  they  are  in 
water ;  and  it  seems  natural  that  the  membrane  should 
take  up  a  gas  in  contact  with  it  till  it  is  saturated,  and 
give  it  off  on  the  other  side  if  the  gas  pressure  is  lower 
there.  During  rest  at  sea  level  this  is  in  fact  what 
happens  with  oxygen,  as  well  as  with  every  other  gas 
which  has  been  tested.  The  gas  passes  so  readily  that 
complete  equilibrium  between  the  gas  pressure  in  the 
alveolar  air  and  that  in  the  blood  has  occurred  before 
the  blood  leaves  the  lungs ;  and  the  gas  pressure  in  the 
arterial  blood  is  thus  equal  to  that  in  the  alveolar  air. 
For  C02  and  nitrogen  this  has  been  shown  by  the 
aerotonometer  and  other  methods :  for  oxygen  it  has 
been  shown  by  the  carbon  monoxide  method,  the  aero- 
tonometer method  being  unreliable  for  oxygen. 

But  at  high  altitudes  the  moist  albuminous  material 


62        ORGANISM  AND  ENVIRONMENT 

suddenly  reminds  us  that  it  is  alive :  for  it  begins  to  do 
something  which  at  once  recalls  living  things  when  it 
delivers  oxygen  at  a  higher  pressure  than  that  at 
which  it  receives  it.  The  passage  of  oxygen  molecules 
is  accelerated  in  the  inward  direction,  and  this  accel- 
eration applies  to  them  alone,  and  not  to  other  mole- 
cules, so  it  is  selective.  It  does  not  occur  in  a  non- 
living membrane,  and  its  presence  is  evidently  depend- 
ent, firstly  upon  the  peculiarities  of  the  living  mem- 
brane, and  secondly  upon  the  presence  of  a  special 
stimulus  acting  on  the  membrane.  We  know,  also, 
that  the  specific  peculiarities  of  living  tissues  depend 
upon  the  maintenance  of  their  external  environment. 
Hence  we  can  say  that  the  acceleration  depends,  not 
only  upon  the  factors  just  mentioned,  but  upon  the 
integrity  of  the  general  environment  of  the  mem- 
brane— in  more  familiar  words,  upon  its  nutrition, 
temperature,  etc.,  and  upon  the  regulated  removal  of 
so-called  waste  products. 

Active  secretion  of  oxygen  is  not  a  new  phenomenon 
in  physiology.  It  is  now  over  a  century  since  the 
famous  physicist  Biot  made  the  discovery  that  the  gas 
in  the  swim  bladder  of  deep  sea  fishes  is  nearly  pure 
oxygen.  The  pressure  of  oxygen  in  sea  water  is  only 
about  a  fifth  of  an  atmosphere,  and  is  doubtless  less 
than  a  tenth  of  an  atmosphere  in  the  blood  circulating 
outside  the  walls  of  the  swim  bladder.  Yet  inside  the 
swim  bladder  the  oxygen  pressure  in  the  case  of  deep 
sea  fishes  may  be  100  atmospheres  or  more.  It  was 
shown  in  1877  by  Moreau  that  fishes  secrete  just 
sufficient  oxygen  into  their  swim  bladders  to  bring 


REGULATION  OF  ENVIRONMENT       63 

their  specific  gravity  equal  to  that  of  the  water  at 
whatever  depth  they  may  be,  or  even  to  counterbal- 
ance the  effects  of  a  float  or  weight  attached  to  them. 
I  have  in  my  library  Lud wig's  copies  of  Moreau's 
papers.  They  are  an  interesting  clue  to  what  was 
passing  through  his  mind  in  suggestions  he  made  as 
to  the  possibility  of  oxygen  secretion  in  the  lungs.  It 
was  discovered  by  Bohr  that  the  oxygen  secretion  in 
the  swim  bladder  is,  like  salivary  secretion,  under 
nervous  control ;  and  Dreser  found  that  oxygen  secre- 
tion can  be  excited  by  pilocarpin,  a  drug  which  also 
excites  secretion  in  other  glands. 

The  cells  in  the  wall  of  the  swim  bladder  which 
secrete  the  oxygen  are  columnar,  and  arranged  like 
the  cells  of  many  other  secreting  glands,  whereas  the 
lung  epithelium  is  extremely  thin.  Nevertheless  the 
elementary  structure  of  the  lung  is  glandular,  just  as 
in  the  case  of  the  swim  bladder;  and  both  lung  and 
swim  bladder  are  developed  as  outgrowths  of  about 
the  same  part  of  the  alimentary  canal.  Before  the 
lungs  expand  at  birth  the  lung  epithelial  cells  are  cubi- 
cal, and  similar  to  those  of  other  secreting  glands. 
That  the  secreting  cells  should  be  thicker  in  the  swim 
bladder  is  natural  considering  the  enormously  greater 
pressure  against  which  the  cells  have  to  secrete. 

The  pressure  difference  against  which  oxygen  can 
be  secreted  in  the  lungs  is  evidently  quite  limited.  This 
is  shown  by  measurements  of  the  oxygen  pressures  in 
the  blood  in  CO  poisoning,  when  the  stimulus  to  secre- 
tion is  pushed  up  to  what  is  presumably  a  maximum. 
If  there  were  no  limit  the  secretion  of  oxygen  would 


64        ORGANISM  AND  ENVIRONMENT 

afford  complete  protection,  similar  to  that  produced, 
as  already  described,  when  the  oxygen  pressure  of 
the  arterial  blood  is  greatly  raised  by  placing  the  ani- 
mal in  compressed  oxygen.  The  pressure  difference 
against  which  oxygen  can  be  secreted  in  the  lungs  is 
also  dependent  on  the  pressure  of  oxygen  in  the  alveo- 
lar air.  When  this  becomes  very  low  the  pressure  dif- 
ference is  diminished ;  and  the  flow  of  oxygen  may  be 
actually  reversed  if  the  alveolar  oxygen  pressure  is 
low  enough.  A  similar  reversal  seems  to  occur  in  the 
case  of  the  swim  bladder;  and  sometimes  the  air  in 
the  swim  bladder  seems  to  be  utilized  as  a  store  of 
oxygen,  drawn  upon  when  the  blood  is  insufficiently 
oxygenated  by  the  gills.  Possibly  the  active  secretion 
current  is  reversed  in  direction. 

Let  us  now  compare  the  secretion  of  oxygen  with 
that  of  other  substances  by  other  secreting  glands.  In 
the  case  of  the  kidney,  various  salts  and  crystalloid 
substances,  particularly  urea,  are  actively  secreted  by 
the  gland  cells,  so  that  their  concentration  in  the 
urine  is  far  greater  than  in  the  blood.  For  instance 
there  is  usually  about  ten  or  fifteen  times  as  much 
urea  in  a  given  volume  of  urine  as  in  the  same  vol- 
ume of  blood,  and  when  the  kidneys  secrete  sugar 
there  may  be  twenty  or  thirty  times  as  much  sugar 
in  the  urine  as  in  the  blood.  Here  then  we  have  other 
cases  of  the  flow  of  one  kind  of  molecules  being  accel- 
erated in  one  direction.  In  the  kidney  secretion  we 
also  see  that  the  acceleration  may  be  in  either  direc- 
tion, and  that  it  depends  upon  the  molecular  concen- 
trations in  the  liquids  on  the  two  sides  of  the  secreting 


REGULATION  OF  ENVIRONMENT       65 

cells.  We  cannot  by  any  means  force  up  indefinitely 
the  concentration  of  a  substance  in  the  urine;  and  if 
the  concentration  in  the  blood  of  a  constituent  of  urine 
falls  below  a  certain  point,  the  secretion  of  that  con- 
stituent ceases.  If,  for  instance,  the  concentration  of 
sodium  chloride  in  the  blood  falls  below  normal,  sodium 
chloride  disappears  at  once  from  the  urine,  though  it 
is  still  abundant  in  the  blood.  Sugar  is  not  secreted 
at  all  by  the  kidneys  unless  its  concentration  in  the 
blood  exceeds  the  normal.  In  both  these  cases  the 
acceleration  is  in  the  opposite  direction  to  secretion, 
so  that  the  passage  of  these  substances  is  actively 
prevented. 

The  secretory  action  of  the  kidneys  is  strikingly 
dependent  in  other  ways  on  the  environment  of  the 
secreting  cells.  Their  activity  is  easily  abolished  by 
want  of  oxygen,  for  instance,  or  by  minute  doses  of 
various  poisons,  and  may  be  increased  by  the  admin- 
istration of  various  drugs. 

When  we  look  at  other  cases  of  secretion  we  find 
that  often  enough  some  one  or  other  of  the  sub- 
stances secreted  is  not  present  as  such  in  the  blood, 
but  is  formed  in  the  secreting  cells.  Instances  of  this 
are  the  formation  and  secretion  of  hippuric  acid  in 
the  kidney,  of  urea,  bile  acids  and  pigments  in  the 
liver,  or  of  casein  and  milk-sugar  in  the  milk  glands. 
The  constituents  or  precursors  of  these  substances 
are  taken  up  from  the  blood,  and  their  combination  or 
decomposition  takes  place  in  the  secreting  cell.  The 
resulting  substances  are  then  accelerated  outwards 
from  the  secreting  cell  to  the  duct,  while  their  precur- 


66        ORGANISM  AND  ENVIRONMENT 

sors  are  accelerated  inwards  from  the  blood  into  the 
cell. 

The  step  from  secretion  to  the  processes  which  we 
commonly  designate  as  cell  nutrition  or  cell  respira- 
tion is  only  a  short  one.  The  microscopic  study  of 
secreting  cells  shows  that  the  substances  secreted,  or 
their  immediate  precursors,  are  often  stored  up 
for  some  time  until  the  moment  for  their  discharge 
comes.  This  storage  is  comparable  to  ordinary 
growth.  In  his  famous  book  on  Secreting  Glands, 
published  in  1830,  Johannes  Miiller  expressed  the 
opinion  that  secretion  and  growth  are  merely  different 
aspects  of  one  kind  of  activity;  the  sole  difference 
being  that  in  secretion  the  product  is  removed,  while 
in  growth  it  remains.  Miiller  was  a  vitalist,  and  his 
ideas  on  secretion  were  for  the  time  swept  away  by 
the  whirlwind  of  mechanistic  speculation  which  passed 
over  physiology  about  the  middle  of  the  last  century ; 
but  in  the  main  he  was  right.  We  now  know  that  even 
in  ordinary  nutrition  nothing  remains  still  and  inactive. 
Living  structure  is  really  alive  and  full  of  molecular 
activity:  it  is  the  expression  of  the  directions  and 
velocities  which  this  activity  takes.  Substances  are 
constantly  being  taken  up  from  and  given  off  to  the 
environment;  and  even  when  these  substances  do  not 
seem  to  be  used  up  in  adult  nutrition,  as  for  instance  in 
the  case  of  inorganic  salts,  there  is  a  constant  molec- 
ular interchange  between  the  cell  and  its  environ- 
ment. This  is  proved  by  the  fact  that,  as  was  first 
shown  in  particular  by  Sidney  Ringer,  the  tissues  are 


REGULATION  OF  ENVIRONMENT       67 

extremely  sensitive  to  the  slightest  changes  in  the 
concentrations  of  inorganic  salts  in  their  environment. 

Cell-secretion,  cell-respiration,  and  cell-nutrition  are 
clearly  only  different  aspects  of  the  same  whirl  of 
molecular  activity.  Where  secretion  or  nutrition  seems 
to  be  stationary,  there  is  in  reality  only  a  balance 
between  ingoing  and  outcoming  molecular  streams. 
Instances  of  this  occur  when  the  kidney  is  not  secret- 
ing chlorides,  or  when  no  oxygen  is  passing  into  or 
out  of  the  swim  bladder,  or  when  all  external  activity 
is  latent,  as  in  a  dry  seed.  The  apparent  stand-still  is 
similar  to  that  in  a  blood  corpuscle  in  a  test  tube  of 
blood  half  saturated  with  oxygen,  when  the  stream  of 
oxygen  molecules  entering  the  corpuscle  is  balanced 
by  the  stream  leaving  it.  The  unstable  oxyhemo- 
globin molecules  in  the  blood  corpuscle  are  constantly 
losing  oxygen  molecules  and  as  constantly  regaining 
others,  so  that  the  half  saturation  of  the  blood  cor- 
puscle with  oxygen  represents  the  average  of  the 
gains  and  losses  of  the  haemoglobin  molecules.  This 
we  can  understand.  But  what  conception  can  we  form 
of  the  molecular  streaming  in  the  living  cell  and  the 
strange  co-ordination  which  the  different  molecular 
streams  exhibit?  I  have  tried  to  indicate  how  this 
problem,  which  will  be  followed  up  in  the  next  lecture, 
rises  directly  out  of  the  fact  of  oxygen  secretion.  But 
meanwhile  we  must  follow  further  various  other  facts 
relating  to  respiration. 

The  evidence  existing  at  present  is  strongly  against 
the  theory  of  active  secretion  of  C02  outwards  by  the 
lung  epithelium.    Krogh's  experiments  gave  very  defi- 


68        ORGANISM  AND  ENVIRONMENT 

nite  results  on  this  point.  In  any  case  we  should 
hardly  expect  to  meet  with  active  secretion  of  C02, 
considering  that  the  breathing  is  regulated  by  the  COa 
pressure  in  the  arterial  blood,  and  that  the  oxygen 
supply  to  the  lungs  is  dependent  on  this  regulation. 
During  very  excessive  muscular  work  it  seems  to  be 
the  oxygen  supply  to  the  body  that  first  begins  to  fail. 
This  is  indicated  by  the  fact  that  in  very  hard  work  the 
alveolar  C02  percentage  begins  to  fall,  and  may  even 
become  lower  than  during  rest. 

The  delicate  and  exactly  regulated  organization  by 
which  C02  is  removed  from  the  blood  in  the  lungs, 
and  oxygen  supplied,  would  quite  clearly  be  of  little 
service  to  the  body  if  there  were  not  also  a  regulation 
of  the  circulation  of  blood  so  as  to  keep  the  removal  of 
C02  from  the  body  tissues  and  their  supply  of  oxygen 
correspondingly  steady.  We  must  now,  therefore, 
consider  what  is  known  as  to  the  circulatory  regula- 
tion. Knowledge  on  this  subject  is  unfortunately  still 
very  fragmentary,  mainly  because  physiologists  have 
failed  to  appreciate  the  delicacy  of  organic  regulation, 
or  have  even  lost  sight  of  it  altogether  when  investi- 
gating various  matters  of  detail. 

The  blood  brings  to  the  tissues  the  various  sub- 
stances required  for  their  normal  life,  and  removes 
from  them  substances  which  are  then  carried  to  other 
tissues  or  to  secretory  organs.  It  is  also  a  carrier  of 
heat.  The  carriage  of  oxygen  and  C02  is  thus  only 
one  of  its  many  functions.  Hence  we  must  not  expect 
that  the  circulation  will  be  solely  regulated  with  refer- 
ence to  the  carriage  of  these  gases.     Bernard  noticed 


REGULATION  OF  ENVIRONMENT       69 

that  during  active  secretion  of  saliva  by  a  salivary 
gland  the  venous  blood  issuing  from  the  gland  was  of 
a  bright  red  colour,  owing  to  quickening  of  the  circu- 
lation ;  and  Barcroft  found  that  owing  to  the  quantity 
of  liquid  and  C02  abstracted  from  the  blood  during 
salivary  secretion  the  absolute  quantity  of  oxygen  in 
a  given  volume  of  the  venous  blood  may  be  greater, 
while  that  of  C02  may  be  less,  than  in  the  arterial 
blood.  As  one  constituent  or  another  assumes  greater 
or  less  importance  in  the  exchange  between  blood 
and  tissues  we  must  expect  the  circulation  to  vary 
accordingly,  and  there  is  no  doubt  that  it  does  so 
vary.  The  gaseous  exchange  is,  however,  every- 
where of  such  immediate  importance  that  we  may  be 
sure  that  the  circulation  is  to  a  large  extent  regulated 
with  reference  to  the  gaseous  exchange. 

The  flow  of  blood  through  any  part  of  the  body 
depends  partly  on  the  difference  in  blood  pressure  be- 
tween arteries  and  veins,  and  partly  on  the  resistance 
to  the  flow  of  blood  from  the  arteries  through  the 
capillaries  to  the  veins.  Now  the  difference  between 
the  pressures  in  the  main  arteries  and  veins  at  any 
given  body  level  is  nearly  constant.  This  is  so  because, 
if  we  neglect  such  part  of  the  pressure  as  is  accounted 
for  by  the  mere  height  above  or  below  the  heart,  the 
pressure  in  the  larger  arteries  is  high,  and  nearly  con- 
stant, while  that  in  the  veins  is  so  low  as  to  be  insigni- 
ficant in  comparison  with  the  arterial  pressure.  Hence 
it  is  through  variations  in  the  resistance  that  variations 
in  the  rate  of  flow  are  brought  about.  But  variations 
in  the  resistance  depend  almost  entirely,  so  far  as  we 


70        ORGANISM  AND  ENVIRONMENT 

know,  on  variations  in  the  calibre  of  the  small  arteries, 
caused  by  variations  in  the  degree  of  contraction  of 
the  circular  muscular  coat  with  which  they  are  pro- 
vided. It  was  discovered  by  Bernard  that  the  muscu- 
lar coat  is  under  the  control  of  the  nervous  system 
through  the  vaso-motor  nerves  supplying  the  arteries. 
It  is  apparently,  therefore,  by  these  nerves  that  the 
rate  of  blood  flow  is  controlled,  though  it  may  be  that 
there  is  also  some  non-nervous  means  of  control,  due 
to  the  direct  local  action  of  chemical  stimuli. 

But  how  are  the  vaso-motor  nerves  themselves 
excited?  It  is  known  that  there  is  a  centre  in  the 
medulla  oblongata  in  connection  with  afferent  nerves 
by  the  excitation  of  which  a  widespread  reflex  aug- 
mentation or  inhibition  of  the  impulses  which  are  con- 
stantly passing  from  the  centre  to  the  arteries  is 
brought  about.  When  this  centre  is  destroyed  or  its 
connections  severed  there  is  also  a  great  general  fall 
in  arterial  blood  pressure  owing  to  dilatation  of  the 
arterioles.  But  the  action  of  this  centre  does  not 
explain  the  local  regulation  of  blood  flow  in  different 
organs  in  accordance  with  local  requirements.  That 
such  local  regulation  occurs  is  known  from  observa- 
tions of  the  local  blood  flow;  it  is  known,  also,  that 
there  are  subordinate  nerve  centres  controlling  local 
blood  supply,  the  response  of  these  centres  being  to 
afferent  impulses  passing  to  the  centres  along  locally 
distributed  nerve-fibres.  The  afferent  nerve-endings 
are  apparently  excited  by  excessive  accumulation  of 
products  of  metabolism  or  by  deficiency  of  the  sub- 
stances  used  up.     It  may  be  that  the  products   of 


REGULATION  OF  ENVIRONMENT       71 

metabolism  act  directly  on  the  walls  of  the  small 
arteries,  but  it  is  somewhat  difficult  to  imagine  how 
this  could  be  brought  about. 

Be  this  as  it  may,  there  is  no  doubt  that  in  some  way 
the  blood  flow  through  different  parts  of  the  body  is 
regulated  in  accordance  with  the  requirements  of  each 
part,  so  that  during  extra  activity  in  any  part  there  is 
a  correspondingly  greater  blood  flow.  Measurements 
of  the  circulation  through  various  organs  have  been 
recently  carried  out,  in  particular  by  Barcroft  and  his 
associates,  in  connection  with  simultaneous  measure- 
ments of  the  oxygen  consumption  in  these  organs. 
The  general  parallelism  between  increased  oxygen 
consumption  and  increased  rate  of  circulation  is  evi- 
dent from  these  measurements. 

To  measure  the  circulation  rate  of  the  body  as  a 
whole  by  direct  means  is  impossible  without  opera- 
tive procedures  which  hopelessly  disturb  the  physio- 
logical conditions.  Indirect  methods  have,  however, 
been  introduced  recently.  One  of  these  is  to  measure 
in  the  lungs  by  a  rapid  method  the  gas  pressures  of 
the  whole  venous  blood  entering  the  lungs.  From  the 
gas  pressures  the  gas  contents  can  be  calculated,  as 
already  seen,  and  a  comparison  of  the  venous  with  the 
arterial  gas  contents  gives  a  direct  measure  of  the 
ratio  between  oxygen  consumption  or  C02  produc- 
tion and  blood  flow.  If  the  amount  of  oxygen  being 
taken  up  and  CO2  given  off  at  the  time  is  known, 
the  blood  flow  itself  can  also  be  calculated.  Using  this 
method  in  man  both  Dr.  Boothby  of  Boston  and  I 
have  found  that  the  blood  flow  increases  proportion- 


72        ORGANISM  AND  ENVIRONMENT 

ately  with  the  consumption  of  oxygen  or  production  of 
C02.  Accordingly  the  differences  in  gas  contents  be- 
tween arterial  and  venous  blood  vary  far  less  than  does 
the  rate  of  metabolism.  To  judge  from  observations 
on  myself,  the  venous  gas  pressures  are  practically 
constant  during  rest.  The  differences  in  gas  pressures 
between  the  two  kinds  of  blood  differ  only  slightly 
with  great  differences  in  the  consumption  of  oxygen. 
The  gross  regulation  of  the  circulation  is  of  such  a 
nature  as  to  keep  the  venous  gas  pressures  nearly 
steady,  while  regulation  of  breathing  keeps  the  arte- 
rial gas  pressures  nearly  steady.  Hence  although  the 
pressure  of  oxygen  is  lower,  and  that  of  C02  higher, 
in  the  venous  than  in  the  arterial  blood,  yet  in  each 
case  the  pressure  is  relatively  steady.  How  the  pecul- 
iar forms  of  the  dissociation  curves  of  oxyhaemoglobin 
and  of  the  compounds  which  C02  forms  in  the  circu- 
lating blood  contribute  toward  this  result  has  been 
explained  in  the  previous  lecture. 

The  rate  of  the  total  circulation  depends  of  course 
on  the  amount  of  blood  pumped  round  by  the  heart; 
and  it  might  seem  at  first  as  if  the  heart  were  the 
prime  regulator  of  the  circulation.  This  mistake  has, 
in  fact,  been  made  by  many  physiologists  through 
failure  to  look  at  physiological  knowledge  as  a  whole. 
Under  normal  conditions  the  heart  simply  maintains 
the  pressure  in  the  large  arteries  by  pumping  more,  or 
less,  blood  according  to  the  rate  at  which  the  blood- 
vessels allow  blood  to  escape.  It  is  thus  the  state 
of  contraction  of  the  blood-vessels  in  the  various  parts 
of    the   body   that   governs   the    rate   of    circulation. 


REGULATION  OF  ENVIRONMENT       73 

The  heart  itself  could  not  act  as  the  prime  regu- 
lator of  the  general  circulation  rate  without  pro- 
ducing great  variations  in  the  arterial  blood  pressure, 
so  as  to  drive  the  blood  at  varying  rates  through 
the  resistance  of  the  arterioles.  These  great  variations 
do  not  normally  exist,  as  is  easily  shown  by  measure- 
ments of  the  blood  pressure.  Nor  would  primary 
regulation  of  the  blood  flow  by  the  heart  be  of  much 
use,  since  any  regulation  brought  about  in  this  way 
would  apply  to  all  parts  of  the  body  alike,  whereas  the 
increased  or  diminished  requirements  for  blood  are 
purely  local,  according  as  one  part  or  another  of  the 
body  is  in  a  state  of  greater  or  less  functional  activity. 

The  heart  is  known  to  be  provided  with  two  sets  of 
nerve  fibres  through  which  its  action  is  controlled,  and 
which  reach  it  as  branches  of  the  vagus  and  the  sym- 
pathetic nerves.  The  vagus  fibres,  when  excited,  exer- 
cise an  inhibitory  action,  reducing  both  the  frequency 
and  the  strength  of  the  heart  beats.  The  very  signifi- 
cant discovery  of  this  inhibitory  action  was  made 
known  by  the  brothers  Weber  in  1845.  Excitation  of 
the  sympathetic  fibres,  discovered  by  von  Bezold  in 
1862,  increases  the  frequency  and  strength  of  the 
heart  beat. 

The  inhibitory  influence  of  the  vagus  fibres  is  at 
once  increased  reflexly  if  the  blood  pressure  in  the 
aorta  (the  great  artery  leaving  the  heart)  rises,  and 
diminished  if  it  falls.  As  an  additional  preventive  to 
excessive  arterial  blood  pressure  there  is  a  further 
nervous  connection  through  which  excessive  rise  of 
blood  pressure  causes  reflex  dilation  of  the  arteries 


74        ORGANISM  AND  ENVIRONMENT 

of  the  intestinal  area,  so  that  the  pressure  is  relieved. 
The  accelerator  or  augmentor  nerve  fibres  are,  ac- 
cording to  recent  investigations  by  Bainbridge,  brought 
reflexly  into  action  by  rise  in  the  pressure  in  the  great 
veins  opening  into  the  heart. 

It  is  clear  also  that  the  amount  of  blood  pumped 
by  the  heart  must  depend  on  the  supply  of  venous 
blood,  and  there  is  experimental  evidence,  first 
brought  by  Yandell  Henderson,  that  fall  in  venous 
blood  pressure  may  actually  limit  the  heart's  output 
of  blood,  so  that  the  frequency  of  the  heart  beats  is 
no  measure  of  the  rate  of  circulation,  just  as  the 
frequency  of  breathing  is  no  measure  of  the  amount 
of  air  breathed.  In  this  connection  the  state  of  con- 
traction or  relaxation  of  the  walls  of  the  veins  is  a 
factor  of  great  importance.  Yandell  Henderson's 
observations,  part  of  which  are  not  yet  published, 
though  communicated  to  me  verbally,  seem  to  indi- 
cate that  contraction  of  the  peripheral  veins  dams 
back  blood  in  the  capillaries.  Less  blood  passes  on 
to  the  great  veins  and  the  pressure  in  them  becomes 
insufficient  for  the  adequate  filling  of  the  heart. 

The  immediate  causes  of  contraction  of  the  walls 
of  the  veins  are  not  yet  exactly  known ;  but  the  obser- 
vations of  Yandell  Henderson  on  the  influence  of  the 
pressure  of  C02  on  the  circulation  are  extremely  sig- 
nificant. When  the  body  is  greatly  impoverished  in 
C02  by  excessive  artificial  respiration  the  circulation 
fails,  apparently  from  an  inadequate  supply  of  blood 
to  the  heart.  The  simplest  explanation  of  the  facts 
seems  to  be  that  the  tonic  contraction  of  the  walls  of 


REGULATION  OF  ENVIRONMENT       75 


the  veins  is  dependent  inversely  on  the  pressure  of  COz 
in  the  blood.  Accordingly  deprivation  of  C02  leads 
to  contraction  of  veins,  with  resulting  congestion 
of  capillaries  and  a  decrease  in  the  volume  of  the 
blood  in  active  circulation  equalling  that  induced  by 
haemorrhage.  On  the  other  hand,  any  condition,  such 
as  muscular  work,  which  is  accompanied  by  increased 
pressure  of  C02  and  diminished  oxygen  pressure  in 
the  blood  leads  to  dilation  of  the  veins,  and  consequent 
increased  rapidity  in  return  of  blood  to  the  heart, 
with  increase  of  venous  blood  pressure.  What  part, 
if  any,  the  nervous  system  plays  in  this  process,  or 
what  other  substances  beside  C02  are  of  influence, 
there  are  as  yet  no  data  to  enable  us  to  decide.  From 
the  circulatory  phenomena  in  asphyxia  due  to  breath- 
ing air  deprived  of  oxygen  (when  there  seems  to  be 
a  great  increase  of  both  arterial  and  venous  blood 
pressure)  we  may,  however,  infer  that  want  of  oxygen 
is  one  such  factor. 

The  state  of  tonic  contraction  of  the  unstriped 
muscle  such  as  is  found  in  the  walls  of  blood  vessels 
depends,  doubtless,  on  many  other  conditions  besides 
nervous  control.  Recent  investigation  shows  that  one 
of  the  most  interesting  of  these  conditions  is  the  supply 
to  the  blood  of  adrenalin,  a  specific  product  of  the 
activity  of  the  suprarenal  glands.  This  discovery 
illustrates  in  a  striking  way  the  interdependence  of 
different  parts  of  the  body — a  subject  to  which  I  shall 
presently  return. 

When  we  review  what  is  known  as  to  the  regulation 
of  the  circulation  it  is  evident  that  it  is  not  primarily 


76        ORGANISM  AND  ENVIRONMENT 

the  heart,  or  the  nervous  system,  which  is  the  regu- 
lator, but  the  metabolic  activity  of  the  body  as  a  whole. 
The  blood  circulates  at  such  a  rate  as  is  sufficient  to 
keep  its  composition  approximately  constant  at  any 
part  of  the  body,  and  the  rate  of  flow  seems  to  be 
greater  or  less  at  any  one  part  in  proportion  as  the 
causes  tending  to  disturb  the  composition  of  the  blood 
are  greater  or  less  at  the  same  part.  Among  the  chief 
of  these  causes  is  consumption  of  oxygen  and  libera- 
tion of  C02.  Hence  the  circulation  rate  is  to  a  large 
extent  determined  by  the  activity  of  the  latter  pro- 
cesses, and  varies,  just  as  the  breathing  varies,  in  such 
a  way  as  to  keep  the  gas  pressures  in  each  part  of  the 
body  approximately  constant. 

This  is  not  an  isolated  fact  in  physiology.  Claude 
Bernard  pointed  out  in  1878  in  his  Legons  sur  les 
phenomenes  de  la  vie  that  the  blood  is  a  fluid  of  re- 
markably constant  composition,  and  practically  pro- 
vides a  constant  internal  environment  for  the  living 
cells  of  which  the  body  of  a  compound  organism  is 
made  up.  He  seems  to  have  been  led  to  this  conclu- 
sion by  his  well-known  studies  on  the  sugar  of  the 
blood.  While  still  under  the  influence  of  the  old  ideas 
of  the  blood  as  a  very  variable  liquid  he  began  his 
investigations  under  the  expectation  that  the  amount 
of  sugar  in  the  blood  would  vary  in  proportion  to  the 
sugar  absorbed  by  the  intestine,  and  would  disappear 
when  no  sugar  or  other  food  was  taken.  To  his 
astonishment,  however,  he  found  sugar  still  abun- 
dantly present  in  the  blood  during  starvation,  and  that 
any   increase   which  he  could   produce  in   the  blood 


REGULATION  OF  ENVIRONMENT       77 

sugar,  by  feeding  with  sugar  or  sugar-forming  mate- 
rial, was  slight.  If  sugar  was  introduced  in  very  large 
quantities  it  was  simply  excreted  in  the  urine.  He 
then  discovered  the  part  played  by  the  liver  in  regu- 
lating the  concentration  of  sugar  in  the  blood,  and  he 
soon  saw  that  other  conditions  of  life  are  similarly 
regulated.  This  led  him  to  express  the  opinion  that 
"all  the  vital  mechanisms,  varied  as  they  are,  have 
only  one  object,  that  of  preserving  constant  the  con- 
ditions of  life  in  the  internal  environment." 

Bernard's  teaching  has  been  to  a  large  extent  for- 
gotten or  obscured  in  masses  of  unconnected  detail, 
but  in  reality  has  been  strikingly  confirmed  by  the 
progress  of  physiology  since  his  time,  and  not  merely 
in  connection  with  the  physiology  of  respiration.  Let 
us  look  at  some  of  the  facts. 

I  will  refer  first  to  the  regulation  of  the  amount  of 
water  in  the  blood,  since  this  is  a  subject  which  Dr. 
Priestley  and  I  have  quite  recently  been  investigating. 
It  is  well  known  that  when  large  quantities  of  water 
are  drunk  an  increasing  secretion  of  urine  follows. 
This  increased  secretion  is  evidently  the  expression 
of  what  may  be  called  metaphorically  the  effort  of 
the  body  to  rid  itself  of  unnecessary  water.  We  made 
a  study  of  the  water  excretion  by  the  kidneys  on  the 
same  lines  as  we  had  followed  in  studying  the  regula- 
tion of  breathing. 

The  increase  in  secretion  of  urine  a  short  time  after 
drinking  a  large  quantity  of  water  is  very  remarkable, 
the  increase  being  usually  to  about  twenty-fold  or 
more,  so  that  as  much  urine  may  be  secreted  in  an  hour 


78        ORGANISM  AND  ENVIRONMENT 

as  is  usually  passed  in  twenty-four  hours.  The  urine 
consists  of  nearly  pure  water,  containing  only  what 
are  relatively  speaking  traces  of  the  ordinary  urinary 
constituents.  Now  this  fact  in  itself  is  very  remark- 
able. The  blood  plasma  contains  a  considerable 
amount  of  sodium  chloride,  and  usually  there  is  more 
sodium  chloride  in  the  urine  than  in  the  blood  plasma ; 
but  in  the  urine  secreted  after  water  drinking  there  is 
hardly  any  sodium  chloride.  The  sodium  chloride  is 
held  back,  while  the  water  passes  in  large  quantities. 

What  we  wished,  however,  to  investigate  specially 
was  the  change  in  the  blood  to  which  the  increased 
secretion  was  a  response.  One  would  naturally  look 
for  evidence  of  dilution  of  the  blood  by  the  water ;  and 
dilution  would  be  shown  by  a  diminution  in  the 
percentage  of  haemoglobin,  since  this  can  be  measured 
with  great  accuracy  and  none  of  the  haemoglobin  is 
excreted  or  destroyed.  There  was,  however,  no 
diminution  in  the  haemoglobin  percentage  during  the 
period  of  most  rapid  excretion  of  the  urine.  Evi- 
dently the  blood  was  not  diluted,  in  spite  of  the  fact 
that  sometimes  a  volume  of  liquid  exceeding  that  of 
the  whole  of  the  blood  had  been  carried  by  the  blood 
from  the  intestines  to  the  kidneys  in  the  course  of 
a  few  hours. 

Dr.  Priestley  then  determined  the  electric  con- 
ductivity of  the  blood  serum,  as  this  gives  a  very 
sensitive  measure  of  the  concentration  of  salts  in  the 
blood.  The  result  was  that  there  was  a  very  slight 
but  constant  diminution  of  the  conductivity  during  the 
extra  secretion.     This  proved  that  though  the  blood 


REGULATION  OF  ENVIRONMENT       79 

was  not  diluted  as  a  whole  there  was  a  very  slight 
diminution  in  the  proportion  of  salts  to  water.  Some 
of  the  salts  had  presumably  passed  from  the  blood 
into  the  water  contained  in  the  intestine,  with  the 
result  of  decreasing  very  slightly  the  percentage  of 
salts  in  the  blood.  The  enormous  extra  secretion  of 
water  was  the  response  of  the  kidney  to  this  very 
slight  change.  At  the  end  of  the  extra  secretion  the 
conductivity  had  returned  to  normal. 

When,  instead  of  pure  water,  a  dilute  solution  of 
sodium  chloride  in  water  was  drunk,  there  was  again 
an  enormously  increased  secretion  of  urine.  This  was 
accompanied  by  an  easily  measurable  dilution  of  the 
blood,  and  the  slightly  increased  conductivity  showed 
that  not  only  water  but  also  salt  was  in  slight  excess 
over  the  other  constituents.  Both  water  and  salt  pass 
out  in  the  urine,  though  at  first  very  little  of  the  salt 
goes,  indicating  that  the  excretion  of  the  extra  water 
is  a  process  independent  of  the  excretion  of  the  extra 
salt. 

After  prolonged  sweating,  so  as  to  deprive  the  body 
of  much  water,  the  urine  becomes  very  scanty  and 
concentrated.  But  in  this  case  the  blood  may  not 
become  measurably  more  concentrated,  even  though 
the  body  has  lost  by  sweating  a  quantity  of  water 
nearly  equal  in  weight  to  the  whole  of  the  blood. 

The  regulation  of  the  proportion  of  water  in  the 
blood  can  thus  be  placed  side  by  side  as  regards  deli- 
cacy with  the  regulation  of  its  reaction  and  compo- 
nents :  its  pressures  of  C02  and  oxygen,  its  percentage 
of  sugar,  urea,  salts,  and  albuminous  substances.    Had 


80        ORGANISM  AND  ENVIRONMENT 

we  the  means  of  determining  the  innumerable  other 
substances  present  in  blood  we  should  doubtless  dis- 
cover a  similar  delicacy  of  regulation. 

All  parts  of  the  body  seem  to  participate  in  this 
regulation.  We  have  already  seen  how  this  is  so  in  the 
case  of  breathing,  circulation,  and  the  activities  of  the 
kidneys  and  liver.  Recent  investigations  reveal  the 
same  thing  in  connection  with  such  organs  as  the 
thyroid,  suprarenal  and  pituitary  glands.  The  regu- 
lation of  the  blood  temperature  in  warm-blooded  ani- 
mals is  one  of  the  most  striking  instances.  During 
muscular  exertion  the  heat  production  in  the  body 
may  be  increased  six  or  eight  fold,  but  the  tempera- 
ture of  the  arterial  blood  is  only  increased  by  a  quite 
insignificant  amount,  as  increase  in  the  skin  circula- 
tion and  in  the  evaporation  of  moisture  from  the  body 
compensates  for  the  increased  production  of  heat; 
while  if  the  external  temperature  is  varied  the  effects 
on  the  body  temperature  are  also  compensated  by 
changes  in  the  skin  circulation  and  evaporation,  and 
by  variations  in  the  heat-production  of  the  body.  The 
regulation  is  through  the  central  nervous  system,  and 
is  exactly  comparable  to  the  respiratory  regulation  of 
the  blood. 

The  phenomena  observed  after  bleeding  or  transfu- 
sion of  blood  are  of  great  interest  in  this  connection, 
and  have  recently  been  studied  in  some  detail  by 
Boycott  and  Douglas,  using  the  new  method  available 
for  determining  the  total  haemoglobin  and  total  blood 
volume  in  the  body  during  life.  After  bleeding  the 
total  blood  volume  in  the  body  is  very  rapidly  recov- 


REGULATION  OF  ENVIRONMENT       81 

ered.  The  capillary  walls  seem  to  take  up  the  liquid 
and  solid  material  required,  and  this  material  is  at  the 
same  time  reconstituted  so  as  to  produce  blood  plasma 
of  normal  composition.  But  the  regeneration  of  the 
lost  red  corpuscles  is  a  much  slower  process,  so  that  the 
new  blood  is  at  first  very  deficient  in  corpuscles,  and 
several  weeks  may  be  needed  for  their  complete  regen- 
eration. If,  however,  the  bleeding  is  repeated  at  inter- 
vals the  process  of  regeneration  of  corpuscles  becomes 
faster  and  faster,  so  that  frequent  re-bleedings  can 
be  easily  borne  by  the  animal.  Similarly,  if  blood  is 
transfused  from  one  animal  to  another  the  liquid  part 
of  the  injected  blood  is  rapidly  eliminated,  but  not  the 
red  corpuscles.  Hence  for  a  considerable  time  the 
blood  is  abnormally  rich  in  corpuscles.  If,  however, 
the  transfusion  is  several  times  repeated  the  excess  of 
corpuscles  disappears  more  and  more  rapidly.  The 
capacity  of  both  the  blood-forming  and  the  blood-de- 
stroying process  is  thus  increased  by  use.  Young  red 
corpuscles  are  known  to  be  formed  in  the  bone-mar- 
row, while  the  products  of  destruction  of  red  cor- 
puscles are  found  in  the  liver  and  excreted  in  the  bile. 
The  capacity  for  formation  or  destruction  of  corpus- 
cles is  thus  associated  with  the  physiological  activity 
of  these  parts  of  the  body,  but  this  activity  is  evidently 
regulated  with  great  exactitude. 

If  we  look,  not  merely  at  the  internal,  but  also  at  the 
external  activities  of  an  organism  Claude  Bernard's 
generalisation  seems  still  to  hold.  The  co-ordinated 
activities  of  the  senses  and  muscular  system  are  mainly 
directed  to  the  end  of  providing  for  nutrition.    Behind 


82        ORGANISM  AND  ENVIRONMENT 

and  controlling  these  activities  are  the  instinctive  ex- 
citatory or  inhibitory  impulses  which  we  know  as 
hunger,  thirst,  satiety,  discomfort  and  comfort.  These 
impulses  may  be  regarded  as  expressions  of  the  many- 
sided  activities  which  are  all  directed  towards  keeping 
the  internal  and  external  environment  constant. 

On  examining  the  forms  which  vitalism  has  taken 
we  find  that  the  vital  principle  has  been  commonly 
regarded  as  an  influence  which  resists  the  tendencies 
of  physical  and  chemical  influences  to  produce  disin- 
tegration of  the  body  structure.  The  great  chemist 
Liebig,  for  example,  looked  at  the  oxidation  processes 
in  the  body  from  this  point  of  view,  and  regarded  the 
vital  force  as  something  protecting  the  structure  of  the 
body  from  becoming  the  prey  of  oxidation. 

But  let  us  examine  the  whole  matter  more  closely. 
It  is  quite  evident  that  the  activities  of  the  various 
parts  of  the  body  are  not  merely  in  the  direction  of 
maintaining  the  internal  environment  constant,  but 
also  in  the  direction  of  disturbing  it.  The  muscles  by 
their  activity  may  be  engaged  in  obtaining  nutriment 
for  the  body,  but  they  are  also  consuming  this  nutri- 
ment wholesale.  The  kidneys  are  not  merely  remov- 
ing superfluous  or  harmful  material  from  the  blood, 
but  they,  too,  are  consuming  oxygen  and  other  sub- 
stances, and  producing  C02  and  other  metabolic 
products.  This  is  also  true  even  of  the  lungs  and  the 
respiratory  centre,  for  the  respiratory  centre  is  vio- 
lently excited  by  the  products  of  its  own  oxidation 
if  its  blood  supply  is  checked.  Now  when  we  examine 
those   activities   which   tend   to   disturb   the   internal 


REGULATION  OF  ENVIRONMENT       83 

environment  we  find  that  they  are  no  less  persistent 
than  the  activities  which  maintain  its  constancy.  The 
muscles  still  continue  to  consume  oxygen  and  form 
heat,  even  though  they  are  for  the  time  at  rest,  and 
though  all  loss  of  heat  from  them  is  prevented.  The 
kidneys  still  absorb  oxygen  when  they  are  not  secret- 
ing. In  a  sense,  too,  they  are  still  secreting,  even  when 
there  is  no  external  sign  of  secretion,  for  the  absence 
of  external  secretion  is  only  the  expression  of  an  equal 
balance  between  constant  intake  and  constant  output 
of  material.  When  the  muscles  and  sense-organs  are 
not  at  work  on  the  getting  of  food,  or  in  other  con- 
servative processes,  they  seem  to  employ  themselves 
otherwise — for  instance  in  what  we  know  as  play. 

No  physiological  facts  are  more  significant  than 
those  relating  to  the  persistence  of  the  fundamental 
metabolic  phenomena.  In  Liebig's  time  it  was  observed 
that  the  excretion  of  urea  rises  and  falls  with  the 
amount  of  nitrogenous  food  consumed,  although  dur- 
ing starvation  there  is  still  a  certain  minimum  excre- 
tion of  urea.  This  was  interpreted  as  signifying  that 
all  superfluous  nitrogenous  food  simply  falls  a  prey  to 
oxygen,  and  is  wasted.  When,  however,  the  facts 
were  further  investigated  it  was  found  that  within 
wide  limits  the  oxidation  in  the  body  does  not  increase 
or  diminish  with  increase  or  diminution  of  the  nitrog- 
enous food  consumed.  Even  after  long  starvation 
the  oxygen  consumption  per  unit  of  body  weight  is 
practically  undiminished  during  rest.  When  more 
nitrogenous  food  is  consumed  in  the  body  and  oxidised 
to    urea,    less    fat    or    carbohydrate    is    consumed. 


84        ORGANISM  AND  ENVIRONMENT 

Rubner  showed  that  nitrogenous  food,  fat,  and  car- 
bohydrate are  substituted  for  one  another  as  material 
for  oxidation  in  exact  proportion  to  the  energy  which 
they  yield  in  the  body.  The  sum  of  this  energy  per 
unit  of  body  weight  remains  constant  during  rest, 
whether  food  is  given  or  withheld.  Even  when  loss  of 
heat  is  prevented  as  far  as  possible,  the  oxidation  pro- 
cesses in  the  body  remain  sensibly  constant  in  spite  of 
prolonged  deprivation  of  food.  The  diminished  oxida- 
tion of  nitrogenous  material  during  starvation  depends 
simply  on  the  fact  that  the  body  stores  its  energy- 
forming  material  mainly  as  fat,  and  consequently  uses 
up  mainly  fat  during  starvation.  When  all  the  fat 
is  exhausted  there  is  again,  before  death  from  starva- 
tion, a  great  increase  in  the  oxidation  of  nitrogenous 
material.  This  latter  fact  adds  new  emphasis  to  the 
persistence  of  the  oxidation  processes. 

The  internal  environment  which  is  maintained  so 
constant  is  in  reality  the  expression  of  a  balance  be- 
tween activities  which  disturb  and  activities  which 
restore  it.  When  we  speak  of  "the  function"  of  an 
organ  and  regard  this  function  as  what  it  does  to 
restore  the  internal  environment  we  are  thinking  in 
terms  of  an  imperfect  and  misleading  conception  of 
what  that  organ  is,  and  what  an  organism  is:  for  we 
are  thinking  of  only  one  side  of  its  activities  to  the 
exclusion  of  others  which  are  just  as  important.  To 
put  this  into  philosophical  language  we  are  thinking 
abstractly,  or  regarding  only  a  part  of  the  reality  we 
are  dealing  with.     We  can  speak  more  correctly  of 


REGULATION  OF  ENVIRONMENT       85 

the  function  of  a  part  of  a  machine:  for  this  part 
does  nothing  else  than  fulfil  its  function,  provided  the 
machine  is  assumed  to  be  perfect  and  stable.  In  a 
living  organ  however  we  are  dealing  with  something 
of  which  the  functions,  if  we  speak  of  functions,  are 
endless,  since  the  activities  are  endless,  constantly 
seeming  to  grow  in  number  as  we  investigate  further. 
Its  true  function,  to  the  eye  of  a  physiologist,  is  to 
maintain  these  endless  activities  in  balance  with  the 
endless  activities  of  other  organs,  and  not  merely  to 
perform  one  specified  action. 

It  is  evident  that  the  balancing  of  molecular  activi- 
ties on  which  the  maintenance  of  the  internal  environ- 
ment depends  is  centred  in  the  bodies  of  the  cells 
which  make  up  the  living  tissues.  The  composition 
and  volume  of  the  blood  are  the  outcome  of  their 
joint  active  or  passive  influences.  We  are  thus  brought 
back  to  the  problems  of  cell-secretion,  cell-respiration, 
cell-nutrition,  cell-movement,  cell-heat-production — 
problems  which,  as  we  have  already  seen,  are  only 
different  aspects  of  one  problem — that  of  what  may  be 
called  cell-metabolism.  Living  cells  are  the  nodal 
points  of  the  molecular  and  ionic  streams  of  which 
one  outcome  is  the  constant  internal  environment. 
The  living  cells  are  the  seat  of  the  molecular  or  ionic 
accelerations  or  retardations  which  manifest  them- 
selves in  secretion,  and  of  the  main  chemical  changes 
which  express  themselves  as  metabolism  in  its  varied 
outward  forms.  When  we  concentrate  attention  ex- 
clusively on  some  one  detail  of  cell-metabolism  we 


86        ORGANISM  AND  ENVIRONMENT 

necessarily  lose  sight  of  the  co-ordination  which  ex- 
presses itself  in  the  persistence  or  constancy  of  cell- 
structure  and  of  the  internal  environment.  But  the 
co-ordination  is  plain  when  we  look  at  the  phenomena 
as  a  whole,  and  becomes  more  and  more  detailed  the 
more  we  penetrate  towards  the  living  tissue  elements. 

The  phenomena  of  breathing  have  turned  out  to  be 
the  outward  expression  of  one  side  of  the  co-ordinated 
activities  which  we  lump  together  under  the  name  of 
metabolism.  Our  conception  of  breathing  depends, 
therefore,  on  the  ideas  we  can  form  of  this 
metabolism. 

At  the  conclusion  of  this  lecture  let  us  glance  at 
what  may  be  called  physiological  causation.  All  physi- 
ological activities  seem  to  be  in  response  to  external 
or  internal  causes  or  "stimuli."  Physiologists  speak 
of  a  "stimulus"  rather  than  a  "cause,"  since  the  word 
"stimulus"  expresses  the  fact  that  other  external  con- 
ditions determine  the  response  besides  the  stimulus 
itself.  The  response  depends,  not  merely  on  the 
strength  of  the  stimulus,  but  on  the  "excitability"  of 
the  responding  tissue.  In  other  words  the  response 
may  be  partially  or  wholly  inhibited  or  greatly  in- 
creased by  varying  conditions  in  the  environment  of 
the  tissue.  The  character  or  direction  of  the  response 
may  also  depend  on  these  conditions,  or  even  on  the 
strength  of  the  stimulus  itself. 

As  has  been  already  shown,  the  respiratory  centre 
normally  responds  with  rhythmic  inspiratory  and  ex- 
piratory responses  to  the  stimulus  of  a  very  minute 


REGULATION  OF  ENVIRONMENT       87 

diminution  in  the  alkalinity  of  the  blood.  But  the 
duration  of  the  responses  is  modified  by  stimuli  de- 
pendent on  inflation  or  deflation  of  the  lungs,  while 
the  extent  of  inflation  or  deflation  which  is  effective 
in  this  direction  depends  on  the  strength  of  the 
primary  chemical  stimulus.  The  effect  of  this  primary 
stimulus  is  also  dependent  on  the  supply  of  oxygen  to 
the  centre,  and  is  increased  if  the  oxygen  supply  is 
defective.  If  we  prefer  to  put  the  matter  in  another 
way,  deficiency  of  oxygen  is  itself  a  stimulus  to  the 
centre,  but  is  dependent  for  its  effect  on  the  reaction 
of  the  blood,  and  is  quite  ineffective  if  the  alkalinity 
increases  slightly.  Other  substances,  such  as  morphia, 
chloral,  or  chloroform,  diminish  the  responses  of  the 
centre  to  a  given  diminution  in  blood  alkalinity ;  and 
from  the  analogy  of  other  tissues  we  may  be  quite 
sure  that  slight  changes  in  the  concentration  of  the 
salts  and  other  substances  in  the  blood,  or  changes 
in  its  temperature,  must  similarly  affect  the  response 
of  the  centre  in  one  direction  or  another.  We  can  even 
imagine  the  respiratory  centre  responding,  not,  as 
normally,  to  changes  in  alkalinity,  but  to  changes  in  the 
concentration  of,  say,  calcium  salts. 

When  we  seek  for  the  "cause"  of  a  physiological 
reaction  we  are  thus  landed  in  a  maze  of  contributory 
causes.  We  can  wander  in  this  maze  for  as  long  as  we 
like,  but  there  is  no  end  to  it.  So  far  as  it  is  possible 
to  judge,  those  who  seek  in  physiological  phenomena 
for  the  same  kind  of  causal  explanations  as  can 
usually  be  assigned  in  connection  with  inorganic  phe- 


88        ORGANISM  AND  ENVIRONMENT 

nomena  have  no  prospect  but  to  remain  seeking  indefi- 
nitely, unless  they  cut  the  knot  by  relapsing  into  vital- 
ism. 

But  is  there  no  scientific  clue  through  this  apparent 
maze?  Does  not  the  element  of  regulation  which,  as 
we  have  seen  throughout,  is  the  outstanding  feature 
of  biological  phenomena,  furnish  the  clue?  In  the 
next  lecture  this  question  will  be  discussed. 


IV 

ORGANIC  REGULATION  AS  THE  ESSENCE 
OF   LIFE.     INADEQUACY   OF   MECHAN- 
ISTIC AND  VITALISTIC 
CONCEPTIONS 

In  the  previous  lecture  we  saw  that  the  internal 
environment  is  kept  constant  as  the  result  of  a  con- 
tinuous and  extraordinarily  delicate  regulation  of  the 
balance  between  opposing  activities.  What  general 
conception  can  we  form  of  this  balancing  process? 

An  obvious  possible  interpretation  is  that  each  of 
the  various  organs  concerned  in  the  balancing  process 
has  such  a  physical  and  chemical  structure  that  it 
reacts  to  a  given  small  deviation  in  the  internal  en- 
vironment so  as  to  prevent  further  deviation  in  this 
direction.  As  the  combined  result  of  the  reactions  of 
all  the  organs  the  internal  environment  as  a  whole 
remains  constant.  It  is  evident,  for  instance,  that  the 
respiratory  centre  reacts  to  very  small  differences  in 
the  hydrogen  ion  concentration  in  the  blood,  in  such  a 
way  as  to  prevent  larger  differences  from  occurring. 
The  temperature-regulating  centre  reacts  to  small  dif- 
ferences in  the  blood-temperature.  The  kidneys  react 
in  a  similar  way  to  very  small  differences  in  the  con- 
centrations of  water,  urea,  and  numerous  other  inor- 


90        ORGANISM  AND  ENVIRONMENT 

ganic  or  organic  substances.  The  organs,  such  as  the 
liver,  or  fat-containing  tissues,  in  which  material  is 
stored,  appear  to  behave  similarly;  and  we  have  now 
every  reason  to  believe  that  we  should  find  the  same 
regulating  activity  in  every  organ  or  part  of  the  body 
if  our  methods  of  investigation  were  sufficiently  deli- 
cate, and  we  knew  the  small  differences  to  be  detected. 
In  every  direction  the  progress  of  physiology  and 
pathology  is  revealing  the  astounding  delicacy  and 
complication  of  the  regulating  processes. 

Up  to  a  certain  point  we  can  rest  satisfied  in  the 
idea  that  the  regulation  of  the  internal  medium  de- 
pends upon  the  specific  structures  and  corresponding 
reactions  of  the  organs  which  bring  about  the  regula- 
tion. But  the  more  we  learn  about  the  delicacy  and 
complexity  of  the  regulating  processes,  the  more  defi- 
nitely does  a  difficulty  appear.  It  is  not  for  nothing 
that  the  body  regulates  its  internal  environment  so 
exactly.  The  investigations  which  reveal  the  exacti- 
tude of  the  regulation  reveal  equally  its  fundamental 
importance  to  the  nutrition  and  normal  working  of 
every  part  of  the  body.  The  organs  and  tissues  which 
regulate  the  internal  environment  are  themselves 
centres  of  nutritional  activity,  dependent  from  moment 
to  moment  on  their  environment.  They  are  constantly 
taking  up  and  giving  off  material  of  many  sorts,  and 
their  "structure"  is  nothing  but  the  appearance  taken 
by  this  flow  of  material  through  them.  The  fact  has 
already  been  referred  to  that  when  the  supply  of 
oxygen  to  the  tissues  is  seriously  restricted  the  result 
is  not  merely  a  slowing  down  of  activity,  but  actual 


ORGANIC  REGULATION  91 

structural  change.  Similar  structural  change  is  known 
to  result  from  many  other  slight  alterations  in  the 
composition  of  the  blood ;  and  so  far  as  the  evidence 
goes,  it  points  to  the  conclusion  that  the  specific  struc- 
ture of  every  part  of  the  body  depends  upon  the  spe- 
cific composition  of  the  blood,  as  well  as  on  the  influ- 
ence of  the  adjacent  tissues  or  external  environment. 
The  regulation  by  the  tissues  and  organs  of  the  inter- 
nal environment  is  thus  only  their  regulation  of  their 
own  structure  and  activity. 

A  living  organism  has,  in  truth,  but  little  resemblance 
to  an  ordinary  machine.  The  individual  parts  of  the 
latter  are  stable,  within  very  wide  limits  of  immediate 
environment,  and  in  no  way  dependent  on  whether 
the  machine  is  in  action  or  at  rest.  This  stability  does 
not  exist  in  the  living  organism.  We  find,  it  is  true, 
that  the  living  organism  may  react  in  a  constant  man- 
ner to  a  given  change,  just  as  a  machine  might  do ;  but 
on  investigation  this  turns  out  to  be  because  the  inter- 
nal environment  is  at  the  time  constant  or  "normal." 
Were  it  otherwise  not  even  the  superficial  resemblance 
would  hold.  As  we  have  seen,  for  example,  in  the 
case  of  the  respiratory  centre,  this  reasoning  applies 
to  nervous  reactions  just  as  much  as  to  other  physi- 
ological reactions. 

It  seems  clear,  therefore,  that  we  cannot  base  our 
explanation  of  the  constancy  of  the  internal  environ- 
ment on  the  structure  of  the  organs  which  regulate 
it,  since  closer  examination  shows  that  the  "structure" 
of  these  organs  is  itself  dependent  on  the  constancy 
of  the  internal  environment.     We  are  only  reasoning 


92        ORGANISM  AND  ENVIRONMENT 

in  a  circle  when  we  attempt  to  explain  the  constancy 
of  the  internal  environment  by  the  specific  characters 
of  bodily  structure.  The  fact  is  that  both  the  internal 
environment  and  the  "structure"  of  the  body  remain 
approximately  constant;  but  of  this  fact  no  explana- 
tion has  been  reached. 

The  explanation  cannot  lie  in  the  external  environ- 
ment, since  this  is  far  less  constant  than  the  internal 
environment,  which  it  constantly  tends  to  disturb. 
It  is  nevertheless  the  case  that  the  external  environ- 
ment, in  so  far  as  it  is  in  relation  with  the  organism, 
exhibits  constancy.  The  composition  and  amount  of 
the  food  and  drink  in  the  alimentary  canal  approxi- 
mate to  a  certain  average;  the  partial  pressures  of 
oxygen  and  carbon  dioxide  in  the  air  which  is  in 
contact  with  the  body,  in  the  lungs,  remain  also  nearly 
constant  under  most  conditions ;  the  impressions  trans- 
mitted inwards  from  without  are  similarly  more  or 
less  constant  on  an  average;  and  excesses  of  heat  or 
cold  are  generally  avoided.  Just  as  the  internal  en- 
vironment seems,  at  first  sight,  to  be  regulated  by  the 
organism,  so  also  does  the  external  environment,  but 
to  a  far  less  intimate  extent.  In  both  external  and 
internal  environment,  the  regulation  is  the  expression 
of  a  balancing  of  opposing  processes  of  loss  or  gain 
of  material  or  energy ;  and  the  processes  involving  loss 
are  no  less  persistent  on  the  whole  than  those  involving 
gain. 

It  is  mainly  through  the  nervous  system  that  the 
body  is,  in  the  higher  organisms,  in  relation  with  the 
external  environment.     When  we  look  broadly  at  the 


ORGANIC  REGULATION  93 

activities  of  the  nervous  system,  they  are  evidently 
of  such  a  character  that  the  external  environment, 
is  regulated  just  as  is  the  internal  environment.  It  is 
in  virtue  of  these  nervous  activities  that  the  stream 
of  material  and  energy  which  is  constantly  entering 
and  leaving  the  body  is  kept  so  nearly  constant. 
Appetite  and  satiety,  muscular  activity  and  fatigue, 
external  temperature  and  heat  loss,  external  light  or 
sound  or  other  sensory  stimuli  and  the  responses  to 
them,  are  balanced  against  one  another  through  the 
nervous  system.  We  cannot  draw  any  complete  line 
of  separation  between  the  regulation  of  the  internal 
and  that  of  the  external  environment;  for  evidently 
the  one  is  complementary  to,  and  indispensable  to, 
the  other.  Regulation  of  the  external  environment 
is  in  fact  only  the  outward  extension  of  regulation 
of  the  internal  environment,  and  the  ultimate  de- 
pendence on  the  external  environment  of  the  organs 
which  regulate  it  is  as  evident  as  their  more  immediate 
dependence  on  the  internal  environment.  Deficiency 
or  excess  in  normal  stimuli,  normal  nutrition,  normal 
temperature  and  respiratory  exchange,  are  as  impor- 
tant to  the  nervous  system  as  to  other  organs.  The 
environment  determines  the  nervous  reactions,  and  the 
nervous  reactions  the  environment,  but  the  constancy 
or  regulation  which  emerges  is  still  unexplained.  The 
conception  of  an  organism  as  a  mere  labile  structure 
which  determines,  and  is  at  the  same  time  determined 
by,  its  environment  is  unsatisfactory,  for  the  reason 
that  the  specific  persistence  of  life  is  left  unaccounted 
for.    The  facts  must  be  examined  more  closely. 


94        ORGANISM  AND  ENVIRONMENT 

We  have  seen  that  it  is  characteristic  of  an  organ- 
ism to  react  towards  disturbing  influences  in  such  a 
way  as  to  maintain  approximate  constancy  in  its  struc- 
ture, internal  environment,  and  even  external  environ- 
ment. If  the  disturbance  is  merely  slight,  temporary, 
and  of  normal  occurrence,  a  simple  and  normal  com- 
pensating reaction  occurs,  and  everything  seems  after- 
wards to  return  again  to  its  former  state.  But  if  the 
disturbance  is  abnormal,  or  continued,  a  significant 
fact  emerges  more  and  more  clearly:  for  new  and 
apparently  original  compensatory  reactions  arise,  or 
an  ordinary  compensatory  reaction  is  greatly  strength- 
ened, or  supplemented.  The  new  reaction  is  accom- 
panied by  corresponding  structural  change,  which  re- 
mains to  a  greater  or  less  extent  after  the  cause  of 
disturbance  has  disappeared. 

We  are  now  in  contact  with  facts  of  a  sort  which 
tend  to  lie  in  the  background  in  connection  with  the 
customary  laboratory  physiology  of  the  present  time, 
but  which  spring  into  such  prominence  in  common 
everyday  observation,  and  particularly  in  connection 
with  clinical  medicine  and  surgery,  as  to  make  the 
physiology  of  ordinary  text-books  appear  somewhat 
unreal.  In  the  course  of  these  lectures  various  facts 
of  the  class  here  referred  to  have  been  described. 
The  Anglo-American  expedition  to  Pike's  Peak  was 
undertaken  with  the  express  object  of  ascertaining  to 
what  extent,  and  in  what  manner,  the  body  adapts 
itself  to  a  continued  diminished  concentration  of  oxy- 
gen in  the  air  breathed.  The  results  showed  that  new 
adaptations,   apart   from   those   demonstrable   during 


ORGANIC  REGULATION  95 

short  exposures,  come  into  play  during  prolonged  ex- 
posure to  a  diminished  oxygen  concentration.  Another 
striking  instance  of  the  same  class  of  fact  is  in  con- 
nection with  the  effects,  referred  to  in  the  previous 
lecture,  of  repeated  bleeding  or  transfusion  of  blood, 
as  observed  by  Boycott  and  Douglas.  After  repeated 
bleedings  the  animal  replaces  the  lost  blood  with 
increasing  rapidity.  After  repeated  transfusions  it 
gets  rid  of  the  excess  with  corresponding  readiness. 
Presumably  in  the  one  case  there  is  an  increase  in 
the  amount  or  activity  of  the  blood-forming  tissues, 
and  in  the  other  an  increase  of  the  blood-destroying 
tissues. 

We  have  only  to  look  round,  outside  the  limits  of 
the  present  conventional  physiology,  in  order  to  find 
innumerable  instances  of  similar  facts.  Striking  ex- 
amples are  afforded  by  the  phenomena  of  immunity 
to  attacks  by  micro-organisms,  and  to  the  action  of 
poisons.  Still  more  remarkable  instances  are  those 
connected  with  the  recovery  of  function  or  reproduc- 
tion of  tissue  after  injury  or  disease,  or  even  complete 
loss  of  parts  of  the  body.  In  the  higher  organisms 
reproduction  of  lost  parts  is  a  less  prominent  feature 
than  in  lower  organisms,  but  indirect  restoration  of 
function  is  a  fact  of  common  observation,  and  is  in 
some  ways  more  significant  and  remarkable. 

It  thus  appears  that  with  disturbance  of  external  or 
internal  environment,  or  living  structure,  the  reactions 
which  occur  are,  whether  immediate  or  gradual,  of  such 
a  character  that  the  organism  adapts  itself  so  as  to 
maintain,  not  merely  its  existence  as  a  structure,  but 


96        ORGANISM  AND  ENVIRONMENT 

also  its  characteristic  activities  and  relations  to  exter- 
nal environment.  The  life  of  the  organism  may  be 
modified,  it  is  true ;  but  in  the  modification  it  retains  all 
its  essential  characteristics,  so  that  its  identity  is  un- 
mistakable. It  persists  actively,  and  not  merely  pas- 
sively. Without  active  adaptation  everything  would 
tend  to  go  from  bad  to  worse,  as  in  the  case  of  an 
untended  machine. 

If  the  internal  environment  is  interfered  with,  as  by 
loss  of  material  or  the  introduction  of  foreign  or  super- 
fluous material,  the  occurrence  of  adaptive  changes 
is  evident.  If  the  structural  elements  of  the  body  are 
interfered  with,  as  in  local  injuries  or  infective  attacks, 
processes  of  repair  soon  manifest  themselves  at  the 
damaged  point:  the  leaky  and  paralysed  blood-vessels 
become  functionally  competent  again :  exuded  material 
is  absorbed ;  and  the  altered  and  functionally  abnormal 
tissue  elements  and  nerve-endings  return  to  a  normal 
condition.  We  are  gradually  coming  to  realise  how 
intensely  delicate  is  the  adjustment  of  immediate 
internal  environment  and  organised  structure  involved 
in  the  existence  of  normal  conditions,  and  the  more  we 
realise  this  the  more  significant  appears  the  process  of 
recovery  or  adaptation.  Another  point  with  regard  to 
this  process  is  that  if  injury  has  not  gone  too  far  the 
restored  tissues  have  become  more  resistant.  It  is,  for 
instance,  a  well-known  fact  that  the  blisters  and  other 
signs  of  local  injury  produced  by  unaccustomed  hard 
use  of  the  hands  or  feet  are  no  longer  produced  after 
"hardening"  by  practice.  The  tissues  have  become 
adapted  to  the  new  conditions,  and  the  adaptation  is 


ORGANIC  REGULATION  97 

no  mere  "functional"  change,  but  is  also  "structural," 
as  shown,  for  instance,  by  thickening  of  the  epithelium. 

When  structural  elements  are  destroyed  or  actually 
removed,  the  process  of  reproduction  is  limited  in  the 
higher  organisms.  We  then  observe  the  phenomenon 
of  other  parts  with  similar  function  taking  on  the 
special  functions  of  the  lost  part.  Gradual  recovery 
owing  to  other  parts  performing  missing  functions  is  a 
matter  of  everyday  experience  in  Medicine  and  Sur- 
gery ;  and  though  the  evidence  is  to  a  large  extent  still 
indirect,  we  cannot  doubt  that  in  all  such  cases  struc- 
tural changes  are  associated  with  the  functional  adap- 
tation. The  phenomena  of  vicarious  function  are  also 
quite  clearly  adaptive  changes,  i.e.,  changes  of  such  a 
nature  that  the  life  of  the  organism  maintains  as  a 
whole  its  identity. 

When  one  regards  the  facts  of  memory  from  the 
purely  physiological  standpoint  it  is  evident  that 
memory  is  a  phenomenon  of  the  same  nature  as  adap- 
tation. An  experience  or  effort  which  has  been  gone 
through  leaves  its  mark  in  the  body  as  increased  power 
of  reaction  to  a  similar  experience  or  performance  of  a 
similar  effort,  just  as  an  attack  of  an  infectious  disease, 
or  vaccination,  leaves  its  mark  in  a  power  of  quickly 
repelling  a  similar  infection.  Were  it  not  so  memory 
would  be  a  useless  incumbrance. 

In  this  connection  we  may  recall  the  facts  relating 
to  the  effects  of  practice  in  the  carrying  out  of  any 
operation,  such  as  writing,  riding  a  bicycle,  or  playing 
a  musical  instrument.  Here  frequent  repetition  of 
what  was  at  first  a  difficult  and  very  imperfectly  per- 


98        ORGANISM  AND  ENVIRONMENT 

formed  operation  leads  to  its  being  performed  with 
ease  and  certainty,  without  there  being  any  conscious- 
ness of  the  innumerable  details  of  nervous  and  muscu- 
lar adjustment  which  are  involved. 

Of  all  other  analogous  facts  the  most  remarkable, 
in  the  higher  organisms,  are  those  relating  to  reproduc- 
tion of  the  whole  organism.  None  of  the  innumerable 
structures  special  to  the  adult  organism  are  present  in 
the  developing  ovum ;  but  as  if  guided  by  stimuli  which 
awaken  memories  of  its  parents  and  ancestors,  it 
builds  up  the  adult  structures  and  activities  by  degrees, 
often  reproducing  even  the  finest  nuances  in  the 
character  of  either  parent.  In  a  living  organism  the 
past  lives  on  in  the  present,  and  the  stored  adaptations 
of  the  race  live  on  from  generation  to  generation,  wak- 
ing up  into  response  when  the  appropriate  stimulus 
comes,  just  as  conscious  memory  is  awakened. 

Looking  at  all  these  facts  we  are  inevitably  forced 
to  the  conclusion  that  the  life  of  an  organism,  includ- 
ing its  relations  to  internal  and  external  environment, 
is  something  of  prime  reality,  since  it  persists  actively 
and  as  a  whole,  and  moreover  tends  to  do  so  in  more 
and  more  detail  with  enlarging  experience,  so  that  life 
is  a  true  development.  What  persists  is  neither  a  mere 
definitely  bounded  physical  structure  nor  the  activity 
of  such  a  structure.  There  is  no  sharp  line  of  demar- 
cation between  a  living  organism  and  its  environment. 
The  persistence  of  the  internal  environment  and  its 
activities  is,  in  fact,  as  evident  as  that  of  the  more 
central  parts  of  an  organism ;  and  a  similar  persistence, 
becoming  less  and  less  detailed,  extends  outwards  into 


ORGANIC  REGULATION  99 

the  external  environment.  An  organism  and  its  en- 
vironment are  one,  just  as  the  parts  and  activities  of 
the  organism  are  one,  in  the  sense  that  though  we  can 
distinguish  them  we  cannot  separate  them  unaltered, 
and  consequently  cannot  understand  or  investigate  one 
apart  from  the  rest.  It  is  literally  true  of  life,  and  no 
mere  metaphor,  that  the  whole  is  in  each  of  the  parts, 
and  each  moment  of  the  past  in  each  moment  of  the 
present.  Organic  wholeness  covers  both  space  and 
time,  and  in  the  light  of  biological  fact  absolute  space 
and  time,  and  self-existent  matter  and  energy,  are  but 
abstractions  from,  or  partial  aspects  of,  reality. 

We  are  thus  brought  face  to  face  with  a  conclusion 
which  to  the  biologist  is  just  as  significant  and  funda- 
mental, and  just  as  true  to  the  facts  observed,  as  the 
conclusion  that  mass  persists  is  to  the  physicist. 

We  saw  previously  that  the  structure  of  a  living 
organism  has  no  real  resemblance  in  its  behaviour  to 
that  of  a  machine,  since  the  parts  of  a  machine  can  be 
separated  without  alteration  of  their  properties.  All 
of  these  properties  are  also  independent  of  whether  the 
machine  is  in  action  or  at  rest.  In  the  living  organism, 
on  the  other  hand,  no  such  separation  can  be  made,  and 
the  "structure"  is  only  the  appearance  given  by  what 
seems  at  first  to  be  a  constant  flow  of  specific  material, 
beginning  and  ending  in  the  environment.  We  have 
now  seen  that  the  apparent  flow  has  a  persistence  and 
power  of  development  of  its  own,  which  we  cannot 
account  for  by  mere  constancy  in  the  physical  and 
chemical  environment.  What  persists  is  not  mere 
matter  or  energy ;  for  the  matter  and  energy  which 


100      ORGANISM  AND  ENVIRONMENT 

seem  to  pass  through  an  organism  are  constantly  being 
replaced.  Nor  is  it  mere  form :  for  the  flowing  mate- 
rial is  intensely  specific.  Structure,  composition  and 
activity  are  inseparably  blended  together  in  life,  and 
no  phenomenon  in  the  inorganic  world  seems  to  us  to 
be  similar  to  the  phenomenon  of  life.  The  funda- 
mental facts  with  regard  to  life  do  not  fit  into  the 
conceptions  by  means  of  which  we  at  present  interpret 
inorganic  phenomena.  Life  is  something  which  the 
biologist  as  such  must  treat  as  a  primary  reality,  and 
no  mere  artifact.  It  is  with  life,  and  not  merely  with 
physics  or  chemistry,  or  bio-physics  or  bio-chemistry, 
that  these  lectures  have  dealt.  From  the  outset  of  my 
own  scientific  work  I  have  been  guided  by  the  concep- 
tion that  it  is  with  life,  and  not  with  what  physics  and 
chemistry  are  at  present  capable  of  interpreting,  that 
physiology  deals ;  and  this  conception  has  grown 
clearer  in  my  mind  as  a  scientific  working  hypothesis 
with  advancing  experience  as  a  physiological  worker. 
What  aims  does  this  conception  carry  with  it  for 
physiological  investigation?  The  ground  hypothesis 
or  conception  is  that  each  detail  of  organic  structure, 
composition,  and  activity  is  a  manifestation  or  expres- 
sion of  the  life  of  the  organism  regarded  as  a  separate 
and  persistent  whole.  We  have  therefore  to  make 
use  of  this  hypothesis  as  a  tool  for  investigation,  just 
as  the  physicist  uses  the  conceptions  of  mass  and 
energy,  or  the  chemist  the  atomic  theory.  We  assume, 
therefore,  that  it  will  be  found  on  sufficient  investiga- 
tion that  the  scattered  observations  of  living  organisms 
with  which  preliminary  sensory  observations  supply 


ORGANIC  REGULATION  101 

us  are  capable  of  unification  under  our  guiding 
hypothesis ;  and  we  proceed  to  investigate  them  further 
with  this  faith  present  to  us.  We  notice,  for  instance, 
that  animals  breathe.  The  breathing  is  a  manifesta- 
tion of  the  animal's  life,  for  any  hindrance  to  breath- 
ing is  violently  resisted  with  the  animal's  whole 
available  power.  Further  investigation  shows  us  more 
definitely  what  breathing  is,  the  essential  element  in 
breathing  being  the  due  supply  of  oxygen  to  the  body, 
and  removal  of  carbon  dioxide.  By  more  detailed 
investigations,  such  as  I  have  endeavoured  to  describe 
in  these  lectures,  we  reach  a  further  knowledge  of  how 
the  phenomena  of  breathing  are  integral  manifesta- 
tions of  the  whole  life  of  the  organism,  including  its 
past  history ;  and  the  aim  remains  before  us  of  reach- 
ing similar  knowledge  of  how  the  development,  main- 
tenance and  functional  efficiency  of  each  structural 
element  are  regulated. 

One  of  the  earliest  steps  in  this  voyage  of  discovery 
is  to  find  any  detail  of  structure  or  activity  that  can 
be  regarded  as  a  "normal."  We  look  for  normal 
structure,  normal  chemical  composition,  and  normal 
standards  of  activity.  And  we  do  so  because  we  know 
that  life  maintains  itself:  that  this  maintenance  ex- 
presses itself  in  normals  for  everything  connected  with 
life.  In  the  inorganic  world  there  appear  to  be  no 
normals  in  this  sense;  and  chance,  not  order,  seems, 
to  the  present  very  limited  vision  of  physical  science, 
to  reign  supreme. 

When  we  have  found  what  appears  to  be  a  normal, 
such,  for  instance,  as  a  normal  concentration  of  carbon 


102      ORGANISM  AND  ENVIRONMENT 

dioxide  in  the  alveolar  air,  we  first  test  it  under  vary- 
ing conditions  so  as  to  make  sure  of  its  relative 
stability,  and  then  proceed  to  investigate  its  connection 
with  and  subordination  to  other  normals.  Thus  we 
find  that  the  normal  concentration  of  carbon  dioxide 
in  the  alveolar  air  is  connected  with  or  subordinate  to 
the  normal  composition  of  the  blood,  the  normal 
activity  of  the  respiratory  centre,  heart,  kidneys,  and 
other  organs,  the  normal  composition  and  amount  of 
the  food  and  the  normal  concentration  of  oxygen  in 
the  air.  Our  general  working  hypothesis  would  have 
told  in  a  general  way  that  connections  of  this  kind 
must  exist;  but  special  investigation  could  alone  tell 
us  how  they  exist  and  how  one  is  directly  subordinate 
to  another.  It  is  this  kind  of  investigation  that  is 
experimental  physiology.  The  normals  of  anatomy 
are  not  mere  physical  structure,  nor  are  the  normals  of 
physiology  mere  averages :  they  are  manifestations  of 
the  life  of  an  organism  regarded  as  a  whole.  We 
have  seen,  for  instance,  in  the  case  of  the  alveolar 
carbon  dioxide  pressure,  in  the  percentage  of  haemo- 
globin in  the  blood,  in  the  structure  of  bone-marrow, 
how  a  subordinate  normal  alters  as  the  organism 
adapts  itself  so  as  to  preserve  its  more  fundamental 
normals  under  new  conditions.  In  pathological  condi- 
tions we  find  remarkable  alterations  in  subordinate 
normals,  and  these  alterations  are  undoubtedly  the 
expression,  to  a  large  extent,  of  adaptations  to  the 
altered  conditions.  Pathological  phenomena  are  not 
mere  chance  effects  of  the  environment  on  the  organ- 


ORGANIC  REGULATION  103 

ism.     Pathology  is  a  real  science,  and  part  of  the 
science  of  biology. 

Anatomy  and  physiology,  but  more  particularly 
anatomy,  have  become  hide-bound  in  the  conception 
that  living  structure  is  simply  physical  structure;  and 
in  consequence  of  this  anatomy  has  for  the  present 
the  aspect  of  almost  a  dead  science,  in  spite  of  the  new 
life  impulse  from  experimental  embryology.  The  time 
has  come  for  biology  to  liberate  herself  and  step  forth 
as  a  free  and  living  experimental  science,  with  a  world 
before  her  to  conquer  by  the  help  of  clearer  ideas  of 
what  life  is,  and  how  it  can  be  investigated. 

Biology  is  no  inexact  science,  contented  with  rough 
pictorial  approximations.  The  bane  of  physiology  in 
the  past  has  been  inexact  measurement  and  imperfect 
observation.  The  new  physiology  will  be  different. 
Its  measurements  and  observations  will  be  more  exact, 
and,  as  has  been  shown  in  the  previous  lectures  from 
actual  instances,  of  a  delicacy  often  far  exceeding  that 
of  existing  physical  and  chemical  methods.  But  the 
observations  and  measurements  will  not  be  of  phe- 
nomena which  if  isolated  are  mere  illusions.  The  new 
physiology  will  not  be  content  with  causes,  but  will 
seek  out  the  organisation  of  which  "causes"  are  only 
the  outward  appearance. 

For  the  reasons  already  given,  organism  and  en- 
vironment cannot  be  separated  in  considering  life. 
But  we  seem  to  be  able  to  reach  a  satisfactory  inter- 
pretation of  the  physics  and  chemistry  of  the  external, 
and  even  of  the  internal  environment,  when  these 
states   are   looked   at  apart   from   their   relations   to 


104      ORGANISM  AND  ENVIRONMENT 

organic  activity.  The  oxygen  which  passes  into  the 
lungs  is  just  ordinary  oxygen,  driven  inwards  to  the 
alveoli  by  an  ordinary  atmospheric  pressure  difference. 
The  process  is  organically  regulated,  but  the  regulation 
appears  to  be  something  external  to  the  oxygen,  which 
still  retains  its  usual  properties.  We  can  then  trace 
its  diffusion  into  the  blood,  its  combination  with  haemo- 
globin, its  carriage  onwards  by  the  pumping  action 
of  the  heart,  and  its  dissociation  from  the  haemoglobin 
in  the  systemic  capillaries.  It  has  come  under  more 
intimate  organic  control  in  the  blood,  but  we  can  still 
trace  it  as  molecules  of  ordinary  oxygen.  When  it 
reaches  and  is  absorbed  by  the  tissues  in  cell  metabol- 
ism the  organic  control  becomes  far  more  intimate. 
It  is  caught  up  in  a  whirl  in  which  its  behaviour  is 
from  the  physical  and  chemical  standpoint  utterly  mys- 
terious. We  can  imagine  no  form  of  chemical  com- 
bination which  will  now  explain  the  behaviour  of  the 
oxygen.  The  mental  picture  of  oxygen  atoms  or  mole- 
cules seems  to  fade  away,  and  to  be  replaced  by  an- 
other picture  in  which  organisation  is  not  something 
external  to  organised  material,  but  is  absolutely  iden- 
tical with  the  material,  so  that  both  the  material 
and  its  movements  are  nothing  but  manifestations  of 
the  organisation.  It  is  life  and  not  matter  which  we 
have  before  us. 

We  can  endeavour  to  hold  on  to  the  physical  and 
chemical  picture,  and  to  seek  for  substances  in  the 
living  structure  which  combine  with,  or  enter  into 
other  physical  or  chemical  relations  with  the  oxygen. 
But  a  little  consideration  shows  that  even  if  we  find 


ORGANIC  REGULATION  105 

such  instances,  their  presence  and  formation  is  organic- 
ally determined  by  something  beyond ;  and  of  this 
something  we  can  form  no  physical  or  chemical  pic- 
ture. We  also  realise  more  clearly  that  in  following 
the  physical  and  chemical  picture  of  the  oxygen  from 
the  outset  we  have  only  done  so  by  ignoring  the  organic 
control  which,  though  present,  seems  less  intimate. 
We  have  ignored,  or  put  aside  for  the  time,  the  regu- 
lated maintenance  of  breathing,  the  maintenance  of 
the  delicate  normal  structure  of  the  lungs  and  of  other 
parts  connected  with  breathing,  the  regulation  of  the 
circulation  and  of  the  composition  of  the  blood,  and 
the  maintenance  of  endless  other  things  in  which 
organic  regulation  manifests  itself.  But  when  we 
reach  the  living  tissues  we  can  ignore  the  organic  regu- 
lation no  longer :  for  we  can  see  nothing  clearly  except 
an  evident  manifestation  of  the  most  intimate  organic 
regulation.  The  physical  and  chemical  picture  is 
entirely  obliterated  by  the  picture  of  organism. 

We  may  reflect  that  although  we  cannot  at  present 
trace  the  combinations  into  which  oxygen  enters  in  the 
living  tissues,  yet  the  oxygen  atoms  are  there  in  some 
form.  We  can  demonstrate  their  presence  by  ele- 
mentary analysis,  and  we  can  separate  chemical  com- 
pounds, such  as  proteins,  which  contain  oxygen.  It 
can  therefore  be  only  a  matter  of  further  investigation 
to  discover  how  the  oxygen  and  other  atoms  combine 
in  the  living  tissues  and  how  these  compounds  react 
with  one  another  to  bring  about  the  phenomena  of  life. 
This  reflection  brings  us  very  close  to  a  fundamental 
question.    Physics  and  chemistry  have  brought  us  not 


106      ORGANISM  AND  ENVIRONMENT 

one  step  nearer  to  a  physico-chemical  conception  of  the 
characteristic  phenomena  of  life,  though  they  have 
been  indispensable  in  elucidating  these  phenomena — 
in  enabling  us  to  formulate  with  increasing  sharpness 
and  detail  the  preponderant  and  omnipresent  role  of 
organisation  in  connection  with  biological  phenomena. 
The  more  clearly  we  consider  the  matter  the  more 
clearly  does  it  appear  that  this  failure  is  not  merely 
due  to  lack  of  ordinary  physical  and  chemical  data  of 
the  kind  already  familiar  to  us.  No  such  data  that 
we  can  remotely  conceive  would  help  us :  no  advance, 
for  instance,  in  our  knowledge  of  the  chemical  consti- 
tution and  physical  properties  of  protein  compounds. 
We  can  reach  no  other  conclusion  than  that  it  is  the 
very  conceptions  of  matter  and  energy,  of  physical 
and  chemical  structure  and  its  changes,  that  are  at 
fault,  and  that  we  are  in  the  presence  of  phenomena 
where  these  conceptions,  so  successfully  applied  in  our 
interpretation  of  the  organic  world,  fail  us. 

What  reasons  have  we  for  assuming,  as  we  are  apt 
to  assume,  that  our  physical  and  chemical  conceptions 
or  mental  pictures  of  the  surrounding  universe  corre- 
spond with  reality  ?  The  reason  is  that  they  do  actually 
enable  us  to  predict  much  of  our  experience  of  the 
inorganic  world,  and  up  to  a  certain  point  have  proved 
eminently  reliable.  Nevertheless  they  leave  an  enor- 
mous blank  in  our  knowledge :  for  they  assume  a  world 
of  various  kinds  of  matter  and  various  forms  of 
energy,  variously  distributed ;  but  as  to  why  this  vari- 
ety and  distribution  exist  they  leave  us  in  ignorance. 
From  the  very  nature  of  the  ordinary  conceptions  of 


ORGANIC  REGULATION  107 

matter  and  energy  as  independent  entities  this  igno- 
rance is  unavoidable.  Clear  enough  indications  exist, 
however,  that  the  progress  of  pure  physical  and  chemi- 
cal investigation  is  pointing  towards  truer  and  more 
adequate  conceptions.  The  discoveries  of  the  periodic 
law  and  of  the  transmutations  of  chemical  elements 
in  connection  with  radio-activity  indicate  an  underlying 
connection  between  different  forms  of  matter.  With 
Faraday's  discovery  that  in  electrolytic  dissociation 
the  ions  have  each  a  definite  electrical  charge,  and  the 
more  recent  discoveries  of  the  energy  locked  up  in 
atoms,  and  liberated  as  radio-activity  in  their  decompo- 
sition, an  underlying  connection  between  matter  and 
the  energy  associated  with  it  has  become  no  less  ap- 
parent. Thus  even  if  we  look  only  at  the  evidence 
afforded  by  the  investigation  of  the  inorganic  world  it 
seems  clear  enough  that  our  present  conceptions  are 
only  working  hypotheses: — the  pictures  which  our 
own  generation  has  formed  of  it;  but  only  imperfect 
pictures  not  adequately  representing  reality. 

In  the  organic  world  we  meet  with  something  in 
the  face  of  which  these  working  hypotheses  are  far 
more  definitely  inadequate;  and  the  very  existence  of 
biology  is  a  direct  challenge  to  them.  We  can  never- 
theless see  how  they  can,  up  to  a  certain  point,  be  used 
successfully  in  interpreting  biological  phenomena.  For 
we  can  take  the  structure  of  the  living  body,  not  as 
living  structure,  but  as  something  given  and  independ- 
ent of  its  environment;  and  having  once  made  this 
fundamentally  false  assumption  we  can  proceed  with 
the  investigation  of  the  supposed  physical  structure 


108      ORGANISM  AND  ENVIRONMENT 

in  the  same  way  as  the  physicist  or  chemist  would  pro- 
ceed. This  method  yields  much  provisional  informa- 
tion for  further  investigation  and  more  correct  inter- 
pretation, through  which  real  physiology  advances; 
and  the  mere  possession  of  the  provisional  informa- 
tion is  itself  of  great  value.  By  showing  that  the  living 
body  could  in  certain  respects  be  regarded  as  a  heat- 
producing  machine  Lavoisier  made  a  great  step  for- 
wards, though  he  did  not  realise  that  the  heat-produc- 
tion is  organically  regulated.  For  an  animal  in  normal 
environment  the  hypothesis  that  there  is  a  constant 
relation  between  intake  of  energy  in  the  form  of  free 
oxygen  and  food-material,  and  output  of  energy  as 
heat  and  in  other  forms,  has  stood  the  test  of  the  most 
rigorous  experiments.  The  fundamental  observations 
of  Regnault  and  Reiset,  Pfliiger,  Rubner,  and  others 
have,  however,  shown  that  both  intake  and  output  of 
energy  are  strictly  regulated,  like  other  physiological 
activities ;  and  what  is  implied  in  this  organic  regula- 
tion has  already  been  discussed.  The  preliminary 
comparison  of  the  organism  to  an  energy-transforming 
machine  has  been  of  great  value  in  certain  directions, 
but  has  misled,  and  still  continues  to  mislead,  physiolo- 
gists in  others.  The  real  source  of  the  misunder- 
standing has  been  the  assumption  that  physical  and 
chemical  working  hypotheses  are  more  than  working 
hypotheses  of  limited  profitable  application,  and  accu- 
rately correspond  to  reality  itself. 

This  assumption  has  given  rise  to  the  mechanistic 
theory  of  life  as  a  necessary  corollary,  as  well  as  to 
all  that  is  vaguely  designated  as  "materialism."     But 


ORGANIC  REGULATION  109 

though  the  assumption  is  false  it  must  be  borne  in  mind 
that  working  hypotheses  applicable  to  the  available 
sense  data  are  indispensable  to  the  advance  of  knowl- 
edge and  practice.  With  limited  data  crude  and  simple 
working  hypotheses,  sufficient  to  cover  the  data  with- 
out further  complication,  are  alone  of  practical  use; 
and  both  knowledge  and  practice,  in  dealing  with  iso- 
lated and  imperfect  data,  naturally  proceed  on  crude 
hypotheses.  Where  we  can  as  yet  see  no  organic 
determination  in  isolated  observations  relating  to  life 
the  best  available  description  of  them  is  in  mechanis- 
tic terms  such  as  we  apply  to  the  inorganic  world. 
Such  descriptions  supply  an  indispensable  basis  for 
more  adequate  description  and  interpretation ;  but  to 
give  a  general  application  to  the  crude  working  hypothe- 
ses on  which  these  descriptions  are  based  implies  a 
disregard  of  the  wider  biological  observations  which 
indicate  that  further  investigation  would  reveal  organic 
determination.  This  disregard  is  a  very  marked  fea- 
ture in  current  text-books  of  physiology.  Each  part 
of  physiology,  and  even  each  subdivision  of  a  part, 
is  apt  to  be  treated  in  isolation  from  the  rest,  with  the 
necessary  consequence  that  not  only  is  no  place  left 
for  the  facts  relating  to  organic  determination,  but 
the  isolated  details  are  very  imperfectly  described,  as 
has  been  illustrated  again  and  again  in  the  course  of 
these  lectures. 

The  real  reason  of  this  defect  is  that  physiologists 
have  been  endeavouring  to  fit  their  descriptions  to  the 
imperfect  current  working  hypotheses  of  physics  and 


110      ORGANISM  AND  ENVIRONMENT 

chemistry — an  attempt  which,  in  view  of  the  facts  of 
physiology  can  only  end  in  certain  failure.  They 
assume  as  self-evident,  for  instance,  that  what  they 
are  dealing  with  is  "living  matter."  In  reality  these 
two  words  contradict  one  another.  What  we  interpret 
as  being  in  the  sense  ordinarily  current,  "matter," 
cannot  be  also  interpreted  as  living. 

Why  has  physiology  failed  to  free  herself  from  this 
misunderstanding?  The  fact  of  organic  regulation 
has  been  evident  enough  from  early  times,  and,  except 
in  more  or  less  recent  text-books,  has  received  promi- 
nent attention  from  physiological  writers.  Various 
causes  have,  I  think,  contributed,  and  I  should  like  now 
to  refer  to  one  which  is  specially  prominent. 

The  physiologists  who  laid  most  stress  on  organic 
regulation  adopted  the  theory  known  as  Vitalism — 
a  theory  which,  though  unorthodox,  is  still  very  much 
alive,  and  of  which  the  eminent  experimental  embryol- 
ogist,  Hans  Driesch,  is  probably  the  best-known  living 
representative.  The  vitalistic  theory  is  that  although 
matter  and  energy  are,  whether  outside  or  inside  of  the 
body,  just  what  current  physical  and  chemical  con- 
ceptions describe  them  as,  yet  in  the  living  body  they 
are  guided  by  what  older  physiologists  called  the  "vital 
spirit,"  "vital  force,"  or  "vital  principle,"  and  what 
Driesch1  calls  "entelechy."  As  is  well  known,  Driesch 
discovered  the  fact  that  if  the  constituent  cells  of  an 
embryo  in  its  earliest  stages  of  development  are  dis- 

1  The  clearest  and  shortest  exposition  of  Driesch's  argu- 
ment is,  I  think,  contained  in  his  recent  book,  The  Problem 
of  Individuality,  London,  1914. 


ORGANIC  REGULATION  111 

arranged,  or  separated  entirely  from  one  another,  a 
complete  embryo  may  still  develop,  even  from  a  single 
cell.  He  argues  from  this  and  other  facts  of  analogous 
character,  (1)  that  any  mechanistic  explanation  of  life 
is  unthinkable,  and  (2)  that  we  must  assume  the  inter- 
ference of  a  guiding  influence,  "entelechy,"  which 
directs  the  material  present,  so  that  it  develops  in  the 
right  way. 

Driesch's  destructive  criticism  of  the  mechanistic 
theory  is  particularly  searching  and  cogent,  and  it 
seems  to  me  that  both  he  and  the  older  vitalists  have 
been  justified  up  to  the  hilt  in  refusing  to  accept  this 
theory.  In  the  previous  part  of  this  lecture  I  have 
endeavoured  to  express  the  vitalistic  criticism  in  a 
still  more  general  form  than  it  has  assumed  in  the 
writings  of  the  vitalists.  To  me  the  mechanistic  theory 
of  life  appears  impossible,  not  merely  in  connection 
with  the  facts  of  heredity  and  embryology,  but  at 
every  point  in  biology. 

To  the  vitalistic  theory  itself,  however,  there  are 
insuperable  objections.  Experience  shows  us  that 
where  an  organism  reacts  in  any  way  it  is  always  in 
response  to  some  stimulus,  whether  this  stimulus  origi- 
nates from  without  or  within.  The  stimulus  of  fertili- 
sation normally  initiates  the  segmentation  of  an  ovum, 
and  from  all  analogy  we  must  conclude  that  the  differ- 
ential stimuli  arising  from  neighbouring  cells  or  other 
parts  determine  the  subsequent  differential  behaviour 
of  each  cell  in  the  segmented  ovum.  On  separating  the 
cells  these  differential  stimuli  are  removed,  and  each 
cell  naturally  starts  again  from  the  beginning. 


112      ORGANISM  AND  ENVIRONMENT 

Perhaps  the  case  of  the  respiratory  centre  or  of 
the  kidney  illustrates  as  well  as  anything  else  the  ob- 
jections to  vitalism.  We  have  seen  with  what  marvel- 
lous exactitude  the  respiratory  centre  regulates  the 
hydrogen  ion  concentration  of  the  blood,  but  also  that 
the  response  of  the  centre  is  nevertheless  dependent  on, 
and  proportional  to,  an  increase,  however  small,  in  the 
hydrogen  ion  concentration  of  the  blood.  If  our 
methods  of  measurement  had  been  less  exact,  if,  for 
instance,  we  had  employed  rougher  methods  of  gas 
analysis  in  investigating  the  alveolar  air,  or  if  we  had 
been  compelled  to  rely  simply  on  the  methods,  delicate 
as  they  seem  to  a  chemist,  which  are  at  present  avail- 
able for  measuring  hydrogen  ion  concentration,  it 
might  have  seemed  as  if  the  respiratory  centre  acted 
without  a  stimulus,  guided  by  an  outside  agency,  just 
as  a  locomotive  is  guided  by  the  driver,  who  shuts  off 
or  turns  on  steam  according  to  requirements,  and  thus 
keeps  his  train  up  to  time  in  spite  of  various  accidental 
hindrances.  Vitalism  is  a  theory  of  this  kind:  it 
ignores  the  participation  of  the  environment  in  the 
regulation,  and  consequently  does  not  correspond  to 
the  observed  facts,  and  is  thus  of  little  use  as  a  work- 
ing hypothesis  in  actual  investigation.  Its  only  real 
merit  is  that  it  serves  as  a  means  of  expressing  facts 
relating  to  organic  regulation,  and  the  defects  of 
mechanistic  theories.  These  facts  are  registered  by 
referring  them  to  the  vital  principle  or  entelechy. 

The  further  physiology  seems  to  advance  in  the 
direction  of  mechanistic  explanations  the  more  ob- 
viously it  is  driven  into  vitalism.     For  advance  in 


ORGANIC  REGULATION  113 

mechanistic  explanation  implies  the  assumption  of 
more  and  more  definite  and  complex  physical  and 
chemical  structure  in  the  body,  and  the  development 
and  maintenance  of  this  structure  has  then  to  be 
accounted  for,  with  a  resulting  relapse  into  vitalism, 
whether  acknowledged  or  only  implied.  The  help- 
less struggling  in  this  direction  of  the  mechanistic 
school  which  still  represents  modern  orthodox  physiol- 
ogy will  be  a  marvel  to  future  generations.  It  is  in 
vain  that  the  mechanistic  theorists  endeavour  to  exor- 
cise what  du  Bois-Reymond  called  the  "spectre  of 
vitalism."  This  spectre  is  nothing  but  the  shadow 
cast  by  the  mechanistic  theory  itself — a  shadow  which 
has  only  become,  and  could  only  become,  deeper  the 
longer  the  mechanistic  theory  has  lasted. 

Both  the  mechanistic  and  the  vitalistic  schools  have 
survived  up  to  the  present  day,  but  we  can  under- 
stand that  actual  investigators  have  preferred  to  avoid 
vitalism  so  far  as  they  could,  as  the  vitalistic  hypothe- 
sis seemed  to  set  a  limit  to  experimental  investigation, 
and  they  rightly  and  instinctively  felt  that  there  is  no 
such  limit.  So  long  as  vitalism  seemed  the  only  alter- 
native to  mechanistic  interpretations,  they  were  driven 
towards  the  latter.  In  the  din  of  controversy  between 
vitalists  and  mechanists  there  was,  however,  a  com- 
plete failure  to  go  to  the  root  of  the  matter,  and  en- 
quire into  the  validity  of  the  assumptions  as  to  physi- 
cal reality  which  were  accepted  by  both  sides. 

In  considering  the  facts  of  physiology  we  have 
hitherto  looked  at  them  from  the  standpoint  of  the 
individual  organism  only.     But  we  know  that  in  all 


114      ORGANISM  AND  ENVIRONMENT 

but  the  lower  forms  of  animal  and  vegetable  life  the 
body  is  made  up  of  cells  and  cell-territories,  and  that 
each  cell  is  a  centre  of  life.  The  life  of  the  body  as 
a  whole  is  maintained  by  co-operation  amongst  the 
constituent  cells.  In  the  course  of  the  common  life 
the  individual  cells  are  constantly  perishing  and  being 
reproduced,  but  the  continuity  or  persistence  of  the 
common  life  is  as  evident  throughout  these  changes  as 
throughout  the  nutritive  processes  in  which  the  chemi- 
cal molecules  passing  through  the  body  are  constantly 
being  replaced. 

Not  only  do  the  constituent  cells  reproduce  them- 
selves and  perish,  but  so  does  the  whole  organism  it- 
self ;  and  its  death  is  evidently  just  as  much  a  normal 
phenomenon  as  is  the  death  of  any  of  its  constituent 
cells.  Death  has  sometimes  been  compared  to  the 
wearing  out  of  a  machine,  but  such  a  comparison 
throws  no  light  on  death,  since  the  body  is  not  a 
machine.  Besides  death  and  reproduction,  there  are 
many  other  biological  phenomena  which  show  us  that 
life  is  not  merely  the  life  of  individual  organisms,  but 
the  life  of  a  society  of  organisms.  It  is  the  life  of  a 
family,  and  beyond  that  the  life  of  a  species ;  or  if  we 
endeavour  to  push  the  biological  analysis  still  further, 
the  life  of  the  universe  itself,  though  such  a  life  must 
remain  outside  the  limits  of  clear  mental  vision  until 
we  can  connect  biological  with  physical  and  chemical 
conceptions. 

The  distinctively  biological  conception  which  I  have 
endeavoured  to  formulate  more  definitely  in  these  lec- 
tures enables  us  to  interpret  what  are  ordinarily  re- 


ORGANIC  REGULATION  115 

garded  as  biological  phenomena.  But  the  higher 
organisms,  at  any  rate,  are  also  centres  of  knowledge 
and  volition.  It  is  unmeaning  to  treat  consciousness 
as  a  mere  accompaniment  of  life,  or  to  ignore  the 
differences  between  blind  organic  activity,  and  rational 
behaviour.  Conscious  personality  is  far  more  than 
mere  organism,  and  the  conception  of  life  is  just  as 
inadequate  in  connection  with  personality  as  the  con- 
ceptions of  matter  and  energy  in  connection  with  life. 

It  is  not  the  time  and  place  to  recapitulate  the  rea- 
soning which  leads  to  this  conclusion ;  but  we  may,  per- 
haps, ask  why,  if  the  reasoning  is  correct,  there  is  still 
a  place  for  human  physiology  as  distinguished  from 
psychology.  The  practical  reason  is  that  although  a 
man  is  a  person  and  not  a  mere  organism,  we  cannot 
trace  personality  throughout  all,  or  nearly  all,  of  what 
we  observe  in  a  man.  To  interpret  the  details  as  best 
we  can,  we  have  to  fall  back  on  the  conception  of  life 
in  the  biological  sense,  just  as  in  details  of  what  we 
observe  in  connection  with  living  organisms  we  have 
to  fall  back  on  ordinary  physical  and  chemical  inter- 
pretations. Though  we  know  that  these  interpreta- 
tions on  a  lower  plane  of  knowledge  can  only  be  pro- 
visional, yet  we  should  be  very  helpless  in  practical 
life  without  them.  Their  practical  value  is  unmis- 
takable, and  we  cannot  dispense  with  them.  On  this 
view  the  conflicts  between  materialism  and  spiritual- 
ism, realism  and  idealism,  science  and  philosophy,  are 
only  apparent. 

In  establishing  the  Silliman  Lectures,  the  Founders, 
although  they  left  complete  freedom  to  lecturers  to 


116      ORGANISM  AND  ENVIRONMENT 

treat  their  subjects  as  they  thought  fit,  expressed  the 
wish  that  the  courses  should  have  reference  to  "the 
presence  of  God  in  the  natural  and  moral  world."  It 
is  with  hesitation  that  I  venture  to  refer  to  this  wish : 
for  I  know  that  in  some  ways  my  own  conclusions  are 
probably  different  from  those  of  many  who  have 
thought  very  deeply  on  this  subject. 

In  the  preceding  lectures  I  have  endeavoured  to 
describe  the  results  of  investigations  on  the  physiology 
of  breathing,  and  at  the  same  time  to  show  that  these 
and  other  investigations  lead  to  a  biological  concep- 
tion of  life  which  cannot  be  reconciled  with  the 
mechanistic  conceptions  handed  down  to  us  from  the 
latter  half  of  the  last  century.  I  have  also  argued  that 
in  virtue  of  this  biological  conception  we  must  claim 
for  biology  an  independent  position  as  a  science  deal- 
ing with  the  manifestations  of  an  order  immanent  in 
the  natural  world.  This  order  is  of  a  far  more  inti- 
mate character  than  the  order  hitherto  disclosed  by 
study  of  what  we  at  present  call  the  inorganic  world. 

To  some  men  it  has  seemed  that  the  facts  of  organic 
life  furnish  evidence  of  the  existence  of  an  external 
creator.  The  writings  of  Paley,  for  example,  have 
popularised  this  view.  If,  as  Paley  tacitly  assumed, 
organisms  were  machines  there  would  be  some  basis 
for  this  argument:  for  the  formation  of  the  body 
cannot  be  explained  as  a  physical  and  chemical  pro- 
cess. The  hypothesis  that  the  body  is  formed  in  each 
individual  by  an  act  of  miraculous  creation  would  at 
any  rate  serve  to  stop  a  gap  in  our  knowledge,  though 
a  God  who  did  nothing  but  create  machines  would  be 


ORGANIC  REGULATION  117 

a  mere  Juggernaut.  We  have  seen,  however,  that 
organisms  are  not  machines,  and  with  the  machine 
theory  the  argument,  such  as  it  was,  for  special  crea- 
tion disappears.  Biology  leads  us  to  the  conception,  not 
of  an  external  Creator,  but  of  an  order  immanent  in 
the  natural  world.  This  order  is,  however,  conceived 
as  blind  and  unconscious,  and  cannot,  so  conceived, 
be  identified  with  what  we  have  learnt  to  understand 
as  God. 

It  is  not  from  the  data  of  biology,  and  still  more 
clearly  not  from  those  of  the  physical  sciences,  that 
we  derive  our  conception  of  God,  but  from  the  facts 
of  knowing  and  consciously  doing  which  we  observe 
in  ourselves  and  our  fellow  men  as  conscious  person- 
alities. In  knowledge  the  mind  extends  itself  over 
our  whole  universe,  so  that  what  exists  for  us  exists 
as  known,  however  imperfectly,  and  as  a  sphere  of 
our  activities,  however  imperfect  these  activities  may 
be.  But  we  find  that  neither  knowledge  nor  conscious 
activity  in  general  is  the  mere  knowledge  or  activity  of 
individual  men.  Just  as  the  behaviour  of  the  cells  in 
a  compound  organism  is  unintelligible  if  they  are  con- 
sidered one  by  one,  apart  from  their  relations  to  the 
whole  organism,  so  the  acquisition  of  knowledge  and 
conscious  activity  in  general,  are  unintelligible  from 
the  point  of  view  of  the  individual  man.  We  can 
endeavour  to  picture  to  ourselves  a  man  who  would 
be  entirely  self-centred — who  would  be  a  God  to  him- 
self ;  but  the  attempt  ends  in  failure.  It  is  the  percep- 
tion that  in  us  as  conscious  personalities  a  Reality 


118      ORGANISM  AND  ENVIRONMENT 

manifests  itself  which  entirely  transcends  our  individ- 
ual personalities,  that  constitutes  our  knowledge  of 
God.  In  the  world  of  duty  and  knowledge,  not  in  the 
natural  world  as  such,  we  find  the  God  whom  our 
fathers  have  worshipped,  and  in  whose  strength  they 
have  been  of  good  courage,  and  faced  trouble,  danger 
and  death.    God  is  near  to  us,  and  not  far  away. 

The  facts  of  biology  lead  to  the  conclusion  that  the 
physical  and  chemical  interpretation  of  the  world  is 
fundamentally  imperfect,  however  useful  it  may  be. 
The  biological  interpretation  is  itself  similarly  imper- 
fect in  view  of  the  facts  relating  to  conscious  person- 
ality. But  when  we  regard  the  natural  world,  as  it 
seems  to  me  we  ought  and  must,  not  as  something  com- 
pletely interpreted  in  the  light  of  existing  theory,  but 
as  an  imperfect  interpretation  which  is  the  expres- 
sion of  countless  centuries  of  human  effort,  the  natural 
world  becomes  part  of  the  world  of  duty  and  knowl- 
edge. Natural  science  and  its  applications  are  the 
rough-hewing  in  the  spiritual  world,  and  the  funda- 
mental conceptions  of  each  of  the  natural  sciences  are 
the  tools,  fashioned  by  human  endeavour,  with  which 
this  rough-hewing  is  done.  Scientific  results  are  in 
themselves  only  incomplete  and  abstract  presentations 
of  reality,  just  as  the  stones  are  not  part  of  the  build- 
ing till  they  are  dressed  and  fitted  into  place.  Other 
workers  do  their  part  in  the  building,  but  without  the 
rough-hewing  their  efforts  would  be  in  vain.  Biology, 
for  instance,  is  absolutely  dependent  on  the  preliminary 
work  of  the  physical  sciences,  just  as  other  more  con- 
crete sciences  are  dependent  on  biology.     The  claim 


ORGANIC  REGULATION  119 

is  often  made,  either  explicitly  or  implicitly,  and  in 
our  own  times  particularly  on  behalf  of  the  mathema- 
tical and  physical  sciences,  that  scientific  results  repre- 
sent complete  and  "objective"  reality.  This  claim  can- 
not be  justified. 

We  learn  to  know  God,  not  by  any  process  of  ab- 
stract reasoning  or  external  revelation,  but  by  practic- 
ally realising  in  our  own  everyday  lives,  and  those  of 
our  fellow  men,  that  we  are  not  mere  individuals  but 
one  with  a  higher  Reality.  In  losing  our  individual 
lives  we  find  our  true  life,  and  in  no  part  of  human 
activity  is  this  losing  of  the  individual  self  more  clearly 
realised  than  in  scientific  work.  When,  but  only 
when,  we  see  that  the  natural  world  appears  to  us 
as  it  does  through  the  devoted  scientific  work  which 
has  fashioned  its  present  appearance,  we  have  found 
God  in  the  natural  world.  The  life  of  such  a  man  as 
Charles  Darwin  is  in  truth  a  standing  proof  of  the 
existence  of  God. 

I  think  the  Founders  of  the  Silliman  Lectures  must 
have  felt  this  when  they  left  complete  liberty  to  each 
lecturer  to  treat  his  subject  just  as  seemed  best  for  his 
immediate  purpose,  and  without  reference  to  theology. 


INDEX 


INDEX 


Abruzzi,  Duke  of  the,  58 
Absorption   curve   of   carbon 
dioxide,  constancy  of,  34 
effect    of    dissociation    of 

haemoglobin  on,  33 
in  blood,  32,  33,  34 
Accelerator  nerve,  73 

effect    of    rise    in    venous 
pressure  on,  73 
Acclimatisation,  at  high  alti- 
tudes, 48,  56,  58,  59 
at  high  altitudes,  effect  on 
haemoglobin    percentage, 
51,  52,  56,  57 
at  high  altitudes,  factors  in, 

59 
to  oxygen  want,  47,  48,  49, 

55,  58,  59 
to  repeated  balloon  ascents, 
59 
Acid      poisoning,      ammonia 

formation  in,   39 
Acidosis,  ammonia  formation 
in,  39 
effect  on  alveolar  CO2,  27 
Acids,  effect  on  alveolar  CO2, 
35 
effect  on  breathing,  35 
effect    on    dissociation    of 
oxy-haemoglobin     curve, 
31 


effect   on   respiratory   cen- 
tre, 36 
Activity,  "normal,"  1 
Adaptation,  alteration  of  the 
normal  in,  102 
in  memory,  97 
in  reproduction,  98 
of  epithelium  to  injury,  96 
structural   changes   in,   94 
to  changes  in  environment, 

93,  94,  95,  96 
to  disease,  95,  96 
to  injury,  95,  96,  97 
to  oxygen  want,  94 
to  repeated  bleeding,  95 
to  repeated  blood  transfu- 
sion, 95 
Adrenal,  glands  in  regulation 
of    vaso-constriction,    75, 
80 
Adrenalin,    in    regulation    of 

vaso-constriction,  75 
Aerotonometer,  53 
Aggregation  of  haemoglobin 

by  inorganic  salts,  31 
Air,  supply,  to  divers,  20 
regulation  of,  4 
vitiated,  18 
Albuminous      substances      in 
blood,  as  weak  acids,  32 


124 


INDEX 


Alkali,     effect     on     alveolar 

C02,  35 
effect  on  dissociation  curve 

of   oxyhaemoglobin,   31 
Alps,  50 
Altitudes,   acclimatisation   at, 

48,  56,  58,  59 
alveolar  CO2  at,  47 
alveolar    oxygen    pressure 

at,  61 
arterial  oxygen  pressure  at, 

58,  61 
blood  reaction  at,  50,  51 
circulation  rate  at,  57 
dissociation  of  oxy-haemo- 

globin  at,  50 
effect  of  muscular  exertion 

at,  56 
effect  on  blood  volume,  52 
effect  on  breathing,  47,  48 
effect  of  oxygen  deficiency 

at,  47,  49 
increase  of  red  blood  cor- 
puscles at,  51 
oxygen  consumption  at,  57 
oxygen   pressure   in   blood 

at,  56,  57,  61 
oxygen  secretion  at,  56 
percentage  of  haemoglobin 

at,  51,  52,  56,  57 
secretion     of     oxygen     by 

lungs  at,  53,  54,  56,  57 
Alveolar  air,  CO2  percentage 

in,  8,  9,  10,  11,  12,  13,  14, 

15 
oxygen  pressure  in,  30 
sampling  of,  8 


Alveolar  carbon  dioxide 
and  Hering-Breuer  in- 
hibition,  25 

at  high  altitudes,  47 

calculated  for  dry  air,  14 

constancy  of,  8,  10 

during  severe  exertion,  27, 
41 

effect  of  acids  on,  35 

effect  of  alkalis  on,  35 

effect  of  diabetes  on,  35 

effect  of  diet,  35 

effect  of  increased  oxygen 
pressure  on,  49 

effect  of  oxygen  deficiency 
on,  27 

effect     of     partially     ob- 
structed breathing  on,  13 

effect    on   breathing,   8,   9, 
10,  11,  12,  13,  14,  15 

in  acidosis,  27 

regulation  of  breathing  by, 
7,  9,  11,  14 

relation  to  barometric  pres- 
sure, 14 
Alveolar  carbon  dioxide 
pressure,  and  percentage, 
relation  to  barometric 
pressure,  14 

during  rest,  27 

relation  to  alveolar  oxygen 
pressure,  49 
Alveolar    oxygen,    constancy 
of,  10 

effect  on  breathing,  8 

regulation  of,  10 


INDEX 


125 


Alveolar  oxygen  pressure,  at 

high  altitudes,  61 
Alveoli,    aqueous   vapour   in, 
13,  14 
CO2  percentage  in,  8,  9,  13 
Ammonia,   formation  in  aci- 
dosis, 39 
formation  in  intestines,  39 
in  regulation  of  blood   al- 
kalinity, 38,  39 
Anglo-American     expedition, 

47,  49,  51,  55,  56,  94 
Apnoea,  6,  9,  22 

after    forced   breathing,   9, 

46,  47 
artificial     respiration     dur- 
ing, 25 
chemical,  22 
CO2  in  alveoli  and  arterial 

blood  in,  22,  9 
"vagus,"  22 
Aqueous    vapour,    in   alveoli, 

13,  14 
Arterial  gas  pressure,  71,  72 

regulation  of,  72 
Arterial  pressure,   regulation 

of,  73 
Artificial  respiration,  25 
during  apnoea,  25 
and   Hering-Breuer  inhibi- 
tion, 25 

Bainbridge,  73 

Balloon   ascensions,   acclima- 
tisation in,  59 
effect  of   oxygen  want   in, 
43,  44 


Barcroft,  31,  34,  50,  69,  71 
Barometric     pressure,     rela- 
tion  to   partial   pressure 
of  C02,  13 
relation    of    pressure    and 
percentage     of     alveolar 
C02  to,  14 
Bernard,  C,  3,  45,  68,  70,  76, 

77,81 
Bert,  P.,  13,  44,  49 
Bichat,  3 

Biological  phenomena,  inter- 
pretation of,  107 
Biology,  103,  116,  118 
Biot,  62 
Black,  3 

Bleeding,  effect  on  blood  vol- 
ume and  regeneration  of 
red  blood  cells,  80,  81 
effect  of  repeated,  81,  95 
Blood,    absorption    curve    of 
carbon  dioxide  in,  32,  33, 
34 
arterial  gas  pressure  of,  71, 

72 
as    the    internal    environ- 
ment, 76 
behaviour     of     albuminous 

substances  in,  32 
capacity  for  taking  up  CO2, 

41 
carbon  dioxide  in,  27,  32 
changes  in  lungs,  33 
colour  of,  6,  7 
dissociation  curve  as  reac- 
tion index  of,  31 


126 


INDEX 


temperature  regulation,  80 

function  of,  68 

percentage  of  oxygen  in,  28 

saturation  with  mixture  of 
CO  and  oxygen,  53,  54 

sugar  contents  of,  76,  77 
Blood,     concentration     after 
sweating,  79 

venous  gas  pressure  of,  71, 
72 
Blood  composition,  and  spe- 
cific "structure,"  90,  91 

effect  of  sweating  on,  79 
Blood  flow,  in  organs,  69,  70, 
71 

effect  of  metabolism  on,  70 

relation  to  blood  composi- 
tion, 76 

subordinate    centres    regu- 
lating, 70 
Blood  alkalinity,  36,  38 

at  high  altitudes,  50,  51 

at  low  barometric  pressure, 
51 

dissociation  curve  as  index 
of,   31 

effect  of  diet  on,  37 

in  regulation  of  breathing, 
by,  42 

nitrogen  of  urine  as  index 
of,  39 

regulation  by  ammonia,  38, 
39 
by    "buffer"    substances, 

36 
by  kidneys,  39,  40,  51 
by  liver,  39,  40,  51 


Blood  pressure   and   oxygen 

deficiency,  75 
Blood    reaction     (see    blood 

alkalinity) 
Blood  transfusion,   effect  on 
blood    volume    and    red 
blood  corpuscles,  80,  81 
effect  of  repeated,  81,  95 
Blood   volume   at  high   alti- 
tudes, 52 
effect  of  bleeding  on,  80 
effect    of    transfusion,    80, 
81,  95 
Bohr,  30,  53,  63 
Bone  marrow,  formation  of 
red  blood  corpuscles  in, 
81 
Boothby,  71 
Boycott,  50,  80,  95 
Breathing,  3,  100,  101 
after  excessive  ventilation, 

46,  47 
apnoea  after   excessive,   9, 

46,  47 
at  altitudes^  47,  48 
CO2  in  regulation  of,  7,  9, 

11,  14 
CO2  pressure  in  regulation 

of,  34 
during  exercise,  10 
effect  of  acids  on,  35 
effect  of  alkalis  on,  35 
effect  of  alveolar  CO2  on, 

8,  9,  12 
effect    of    alveolar    oxygen 
on,  8 


INDEX 


127 


effect  of  CO2  pressure  on, 
34 

effect  of  cutting  vagus 
nerves  on,  21,  25,  26 

effect  of  oxygen  deficiency 
on,  42,  43 

effect  of  partial  obstruc- 
tion on  alveolar  CO2,  13 

essential  factors  in,  3 

extent  of  voluntary  con- 
trol, 11 

frequency  relation  to  alve- 
olar CO2,  12 

in  diabetes,  35 

in  regulation  of  alveolar 
C02,  7,  9,  11,  14 

influence  of  vagus  nerve 
on,  21,  22,  23,  24,  26 

influence  of  vagus  nerve  in 
man  on,  23,  24 

"mechanism"  in  regulation 
of,  16 

regulation  of,  7,  9,  11,  14, 
26,  27,  38,  40,  42,  43,  46, 
47 

regulation  of,  in  oxygen 
deficiency,  43 

vagus  nerve  in  regulation 
of,  21,  22,  23,  24 

"vitalism"  in  regulation  of, 
17 
Breuer,  21,  23 

"Buffer  substances"  in  blood, 
36 

in  urine,  40 


Canaries,     in     detection     of 
small  percentages  of  car- 
bon monoxide,  46 
Capillaries,   activity  of  walls 
after  bleeding  and  trans- 
fusion, 80 
passive  congestion  in  regu- 
lation   of    venous    pres- 
sure, 74,  75 
Carbon  dioxide,  3,  4 
absorption  curve  in  blood, 

32,  33,  34 
absorption  in  blood,  41 
absorption  in  blood  during 

violent  exercise,  41 
effect  on  divers,  19,  20 
effects  on  circulation,  15 
in  arterial  blood,  27,  32 
in  chemical  combination  in 

blood  and  plasma,  31 
in    inspired    air,    effect    of 

high  percentage  of,  9 
in    regulation    of    gaseous 

contents  of  blood,  72 
"mass  influence"  of,  32 
regulation     of     circulation 

rate  by,  76 
relation       of       barometric 
pressure  to  partial  pres- 
sure of,  13 
removal  in  a  vacuum,  32 
secretion  by  lungs,  67 
Carbon    dioxide    in    alveoli, 
and  frequency  of  breath- 
ing, 12 
at  high  altitudes,  47 


128 


INDEX 


calculated  for  dry  air,  14 
constancy  of,  8,  10 
during  apnoea,  9,  22 
during  rest,  27 
during  severe  exertion,  27, 

41 
effect  of  acids  on,  35 
effect  of  alkalis  on,  35 
effect  of  diabetes  on,  35 
effect  of  diet  on,  35 
effect  of  hyperpnoea  on,  42 
effect     of      partially     ob- 
structed breathing  on,  13 
effect  on  breathing,  8,  9 
in  oxygen  deficiency,  27 
percentage,  8,  9,  13 
pressure  and  percentage  at 
various  barometric  pres- 
sures, 14 
regulation  during  exercise, 

10 
regulation  of  breathing,  7, 

9,  11,  14 
relation  of  oxygen  alveolar 

pressure  to,  49 
relation  to  barometric  pres- 
sure, 14 
Carbon  dioxide  in  blood,  and 
hydrogen  ion   concentra- 
tion, 37 
dissociation  of,  31 
during  apnoea,  9,  22 
indirect   regulation   by   en- 
dothelial cells,  41,  42 
regulation  of  breathing  by, 
27,  42 


regulation  of  venous  con- 
striction by,  74 

regulation  of  venous  pres- 
sure by,  74,  75 
Carbon  dioxide  deficiency,  in 
"shock,"  15 

symptoms  of,  16 
Carbon  dioxide  excess,  effect 
on  breathing  during  ex- 
ertion, 19 

symptoms  of,  16 
Carbon    dioxide    percentage, 

in  alveoli,  8,  9,  13 
Carbon  dioxide  pressure,  and 
hydrogen-ion    concentra- 
tion of  blood,  37 

at  different  altitudes,  49 

effect  of  increased  oxygen 
pressure  on,  49 

effect  on  dissociation  curve 
of  oxy-haemoglobin,  30, 
31 

regulation  of  breathing,  34 

relation  to  alveolar  oxygen 
pressure,  49 
Carbon   monoxide,    combina- 
tion   with    haemoglobin, 
45 

method  of  determining 
oxygen  pressure  in  blood 
leaving  lungs  with,  54 
Carbon  monoxide,  saturation 
of  blood  with  mixture  of 
oxygen  and,  53,  54 

test  for  presence  of,  46 
Carbon   monoxide  poisoning, 
cause  of,  45 


INDEX 


129 


compressed       oxygen       in 

treatment  of,  45 
in  mines,  18,  45 
oxygen  deficiency  in,  44,  45 
remote  effects  of,  46 
symptoms  of,  46 
Causation,    physiological,    86, 

87,  103 
Cell  metabolism,  85 
Chemical  apnoea,  22 
Chemistry  and  physics  in  life 

phenomena,   105,  106 
Christiansen,  32 
Circulation,  4 
effect  of  CO2  on,  15 
function  of,  68 
in  small  animals,  46 
regulation  of,  68,  69,  73,  75 
Circulation  rate,  and  oxygen 
consumption,  71,  76 
at  high  altitudes,  57 
local    regulation    by    vaso- 
constrictors, 72 
method  of  determining,  71 
of  body  as  a  whole,  71 
regulation  by  CO2  elimina- 
tion, 76 
regulation  by  heart,  72,  73 
regulation  by  oxygen  con- 
sumption, 76 
Clinical  medicine  and  physi- 
ology, 94 
Coal  mines,  gases  in,  7 
Co-ordination    in    physiologi- 
cal activities,  1,  2,  26 
Coxwell,  44 
Croce-Spinelli,  44 


Darwin,  Charles,  119 

Death,  114 

Delage,  G.,  3 

Diabetes,  alveolar  CO2  in,  35 

respiration  in,  35 
Diet,  effect  on  alveolar  CO2, 
35,  37 
effect  on  H-ion  concentra- 
tion of  blood,  37 
Disease,    adaptation    to,    95, 

96 
Dissociation  curve,  constancy 

of,  34 
Dissociation    of    oxy-haemo- 
globin,  29 
at  high  altitudes,  50 
Dissociation    of    oxy-haemo- 
globin  curve,  29,  30,  31, 
34 
and  inorganic  salts  in  red 

blood  cells,  31 
as    index    of    reaction    of 

blood,  31 
effect  of  acids  on,  31 
effect  of  alkali  on,  31 
effect  of  CO2  of  blood  on, 

30,  31 
effect  on  absorption  curve 
of  carbon  dioxide,  33 
Divers,  air  supply  to,  20 
Diving,  effect  of  CO2  in,  19, 

20 
Douglas,  32,  41,  54,  55,  58,  80, 

95 
Dreser,  63 
Driesh,  Hans,  110,  111 


130 


INDEX 


Electric   conductivity   of    se- 
rum after  drinking  dilute 
sodium  chloride  solution, 
79 
after    excessive    water    in- 
take, 78,  79 
Electrolytic  dissociation,  107 
Embryo,  development  of,  110, 

111 
Embryology,       experimental, 

103 
Emphysema,   in   mine   work- 
ers, 19 
Endothelial      cells,      indirect 
regulation     of     CO2     in 
blood  by,  41,  42 
Energy,  and  food  supply,  84 
intake  and  expenditure  of, 
108 
"Entelechy,"  110,  111,  112 
Environment,    adaptation    to 
changes  in,  93,  94,  95,  96 
and    organism,    2,    98,    99, 

103 
external,  92,  93 
external,  regulation  of,  92, 

93 
internal,  blood  as  the,  76 
in    relation    to    function, 

82,  83,  84,  93 
influence  on  response  to 

stimulus,  86 
maintenance  by  cell  me- 
tabolism, 85,  86 
regulation  of,  89,  90,  91 
relation  of  nervous  system 
to,  92,  93 


Epithelial  cells  of  lungs,  gas- 
eous exchange  by,  52,  53 
function  of,  61 
secretion  of  oxygen  by,  53, 

54,  56,  57 
selective  secretion,  62 
Epithelium,  adaptation  to  in- 
jury of,  96 
Erythrocytes    (see  red  blood 

corpuscles) 
Excretion  of  urea,  39,  83 

of  water,  77 
Exercise,  effect  on  breathing, 

10 
Expiration,  cause  of,  22 

Faraday,  107 

Fertilisation,  stimulus  of,  111 
Filippi,  58 

Fitzgerald,  49,  52,  55 
Forced  breathing  and  apnoea, 

9 
Fredericq,  6,  53 
Fredericq's  experiment,  6 

Gas     pressure     in     arterial 
blood,  71,  72 

in  venous  blood,  71,  72 
Gases,  in  coal  mines,  7 

solution  in  liquids,  27 
Gaseous    exchange    by    lung 

epithelium,  52,  53 
Glaisher,  43,  59 
God,  conception  of,  117,  119 
Growth,  secretion  and,  66 


INDEX 


131 


Haemoglobin,  6,  28 

aggregation  of  molecules 
by  inorganic  salts,  31 
behaviour  as  a  weak  acid, 

32 
colorimetric  estimation  of, 

52 
combination       of       carbon 

monoxide  with,  45 
function  of,  7 
percentage,  after  excessive 
water  drinking,  78 
at  high  altitudes,  51,  52, 

56,  57 
effect  of  increased   oxy- 
gen pressure  on,  52 
Hasselbalch,  36,  49,  51 
Heart,  function  of,  72 
nerve  supply,  73 
regulation     of     circulation 

rate  by,  72,  73 
regulation  of  discharge,  74 
sympathetic  control,  73 
vagus  control,  73 
Hemorrhage,   effect   of    (see 

bleeding) 
Henderson,  L.  J.,  40 
Henderson,   Yandell,    15,   25, 

46,  55,  74 
Henry,  law  of,  28 
Hering,  21,  23 

Hering-Breuer  inhibition  and 
alveolar  CO2,  25 
and  artificial  respiration,  25 
Himalayas,  58 
Hook,  6 


Hydrogen  ion  concentration, 
36 

and  CO2  pressure  in  blood, 
37 

effect  of  diet  on,  37 

effect   on   respiratory   cen- 
ter, 37,  89,  111,  112 

under      low      atmospheric 
pressure,  51 
Hyperpnoea,  6 

effect  on  alveolar  CO2,  42 

Immunity     to     micro-organ- 
isms, 95 
to  poisons,  95 
Inspiration,  cause  of,  22 
Intestines,  formation  of  am- 
monia in,  39 
passage  of  salts  into,  after 
excessive  water  drinking, 
78,  79 

Kidneys,  excretion  of  water, 
77 
in  regulation  of  blood  re- 
action, 39,  40,  51 
Kidney  secretion,  64,  65 
effects  of  drugs  on,  65 
effects   of  excessive  water 

drinking  on,  79 
effects  of  oxygen  want  on, 

65 
effects  of  sweating  on,  79 
regulation  of,  89 
Krogh,  53,  57,  67 


132 


INDEX 


Lactic  acid,  formation  during 
muscular  exertion,  35, 
41,  50 
formation  in  oxygen  defi- 
ciency, 35,  50 
in  urine  after  violent  mus- 
cular exertion,  41 

Lavoisier,  3,  108 

Law,  periodic,  106,  107 

Liebig,  82,  83 

Life,  conceptions  related  to, 
100 

Life,  mechanistic  theory  of, 
108,  109,  110,  111,  112, 
113,  116 

Liljestrand,  25 

Lindhard,  49,  51,  57 

Liquids,  solution  of  gases  in, 
27 

Liver,     destruction     of     red 
blood  cells  by,  81 
regulation  of  alkalinity  of 

blood  by,  39,  40,  51 
regulation   of   blood   sugar 
contents  by,  77 

Living  matter,  109,  110 

Living  structures,  character- 
istics of,  66 
molecular  activity  in,  66,  67 

Ludwig,  34,  53,  63 

Lundsgaard,  36 

Lung  epithelium,  gaseous  ex- 
change by,  52,  53 
function  of,  61 
oxygen    secretion    in    rela- 
tion to  CO2  pressure,  62, 
63,  64 


secretion  of  oxygen  at  high 

altitudes,  53,  54,  56,  57 
selective  secretion  by,  62 
Lungs,  4 
blood  changes  in,  33 

"Materialism,"  108 
Matter,  relationship  of,  107 
Mavrogorato,  23 
Mayow,  3 
Mechanism,  2,   99 
and   regulation   of   breath- 
ing, 16 
Mechanistic    theory    of    life, 
108,    109,    110,    111,    112, 
113,  116 
of  regulation,  5 
Medulla  oblongata,  5,  21,  70 
Memory,  adaptation  in,  97 
Metabolism,    effect   on   vaso- 
motor nerves,  70 
in    regulation    of    circula- 
tion, 75 
nitrogen,  83,  84 
of  cell,  85 

on  local  blood  flow,  70 
Micro-organisms,      immunity 

to,  95 
Miners,  effect  of  oxygen  de- 
ficiency in,  43 
emphysema  in,  19 
Mines,  CO  poisoning  in,  45 
CO2  in  air  of,  18 
gases  in,  7,  18,  45 
ventilation  in,  19 
Moreau,  62,  63 
Mountain  sickness,  55 


INDEX 


133 


Miiller,  Johannes,  66 

Muscular    exertion,    at    high 
altitudes,  56 
lactic  acid   formation  dur- 
ing, 35,  41,  50 

Nerve,  vagus,  21,  22,  23,  24, 

25,  26,  73 
Nerves,  vaso-motor,  70 
Nilsson,  25 
Nitrogen  metabolism,  83,  84 

relation  to  urea,  83 
Nitrogen  of  urine,  as  index 

of  blood  alkalinity,  39 
Normals  of  anatomy,  102 
Nutrition,  coordination  in,  81 

Organic  regulation,  108,  110 
Organic  regulation  in  tissues, 

104,  105 
"Organicism,"  3 
Organisation,    manifestations 

of,  104 
Organism,     and     mechanism, 
99 
as  a  machine,  91 
"structure  of,"  99 
Organism    and    environment, 
2,  98,  103 
unity  of,  98,  99 
Oxidation,   and   oxygen   sup- 
ply, 4 
in  starvation,  84 
regulation  of,  4 
site  of,  3,  4 
Oxygen,  3,  4,  7 
alveolar,  8,  10 
regulation  of  supply,  42 


under  compression   in   CO 
poisoning,  45 
Oxygen     consumption,     and 
rate  of  circulation,  71,  76 

at  high  altitudes,  57 

in  starvation,  4,  83 
Oxygen  deficiency,  acclimati- 
sation to,  47,  48,  49,  55, 
58,  59 

adaptation  to,  94 

and  blood  pressure,  75 

at  high  altitudes,  47,  49 

effect    of,    long    continued, 
47 

effect  on  alveolar  CO2,  27 

effect   on  breathing,   7,  42, 
43 

effect  on  kidney  secretion, 
65 

effect  on  physiological   ac- 
tivity, 90 

effect   on   respiratory   cen- 
tre, 47 

formation  of  lactic  acid  in, 
35,  50 

in    balloon    ascensions,    43, 
44 

in  CO  poisoning,  44,  45 

in  mines,  43 

regulation      of      breathing 
during,  42,  43 

symptoms  of,  42,  43 
Oxygen  percentage,   in  alve- 
oli, regulation  of,  10 

in  blood,  28 
Oxygen    pressure,    effect    on 
alveolar  CO2,  49 


134 


INDEX 


effect  on  haemoglobin,  52 

in  alveolar  air,  30 

in    arterial    blood    at   high 
altitudes,  56,  61 

in  blood  leaving  lungs,  by 
CO  method,  54 

in  capillaries   at  high  alti- 
tudes, 57 

in  sea  water,  62 
Oxygen    secretion,    at    high 
altitudes,  56,  57 

by  lung  epithelium,  53,  54, 
56,  57,  63 

in  swim  bladder  of  fishes, 
62,  63,  64 

relation  to  oxygen  pressure 
in  lungs,  63,  64 
Oxy-haemoglobin,      dissocia- 
tion of,  29 

effect  on  absorption  curve 
of  CO2  in  blood,  33 

properties  of,  28 

regulation   of   blood   gases 
by,  72 
Oxy-haemoglobin       dissocia- 
tion curve,  29,  30 

and  CO2  pressure  in  blood, 
30,  31 

and  inorganic  salts  in  red 
blood  cells,  31 

as    index    of    reaction    in 
blood,  31 

at  high  altitudes,  50 

constancy  of,  34 

effects  of  acid  on,  31 

effects  of  alkali  on,  31 


Paley,  116 

Partial  pressure  CO2,  rela- 
tion to  barometric  pres- 
sure, 13 

Pathological  phenomena,  102 

Pathology,  102 

Peak  of  Teneriffe,  50 

Pfluger,  53,  108 

Physics  and  chemistry  in  life 
phenomena,  105,  106 

Physiological  activities,  co- 
ordination of,  1,  2,  26 

Physiology,  and  clinical  med- 
icine, 94 
and  structure,  102 
and  surgery,  94 
definition,  1 
the  "new,"  103 

Pike's  Peak  expedition,  47, 
49,  51,  55,  56,  94 

Pituitary  gland  in  physiologi- 
cal regulation,  80 

Poisons,  immunity  to,  95 

Priestley,  3,  8,  77,  78 

Psychology,  115 

Radioactivity,  107 

Reaction      of      blood      (see 

blood  alkalinity) 
Reaction  of  urine,  40 
Reality,  "objective,"  118 
Red  blood  corpuscles,  28 

at  high  altitudes,  50,  51 

destruction,  81 

effect  of  bleeding  on  regen- 
eration of,  80,  81 


INDEX 


135 


effect  of  transfusion  on,  80, 
81,  95 

formation,  81 

relation      of      dissociation 
curve  to  salts  in,  31 
Regnault,  108 

Regulation,      in      respiratory 
disturbances,   35 

mechanistic  theory  of,  5 

of  air  supply,  4 

of     alveolar     CO2     during 
exercise,  10 

of  alveolar  CO2  in  breath- 
ing, 14 

of  arterial  gas  pressure,  72 

of  arterial  pressure,  73 

of  blood  alkalinity,  36,  38, 
39,  40,  86 

of  blood  alkalinity,  by  am- 
monia, 38,  39 

of  breathing  by  blood  re- 
action, 38,  39,  40,  42 
by  CO2,  7,  9,  11,  14,  26 
by  vagus,  21,  22 
during  excessive  ventila- 
tion, 9,  46,  47 
in  oxygen  deficiency,  43 

of   circulation,    68,    69,    73, 
75 

of  environment,  89,  90,  91, 
92,  93 

of  kidney  secretion,  89 

of  local  blood  flow,  69,  70, 
71 

of  oxidation,  4 

of    oxygen    percentage    in 
alveolar  air,  10 


of  temperature,  80,  89 
of  temperature  in  dog,   13 
of  vaso-constriction  by  ad- 
renals, 75 
of  water  contents  of  blood, 

77,  78,  79 
organic,  104,  105,  108,  110 
vitalistic  theory  of,  4,  17 
Reiset,  108 

Reproduction,  98,  114 
Respiration  (see  breathing) 
Respiration,  artificial,  25 
artificial,       and       Hering- 

Breuer  inhibition,  25 
artificial,  in  apnoea,  25 
effect  of  CO2  pressure  on, 
13 
Respiration   rate,   and   alveo- 
lar C02,  12 
Respiratory  center,  5,  17,  24, 
26,  37,  86,  91,  111,  112 
and    hydrogen-ion    concen- 
tration, 37,  89,  111,  112 
as  index  of  blood  alkalin- 
ity, 38 
blood  constancy  to,  38 
delicacy  of  response,  14,  15 
effect  of  acids  on,  36 
effect  of  alveolar  CO2  on, 

11 
effect  of  drugs  on,  86 
effect  of  excessive  ventila- 
tion, 47 
effect  of  oxygen  deficiency 

on,  47 
factors  affecting,  87 


136 


INDEX 


influence  of  pulmonary  in- 
flation and  deflation  on, 
86,  87 
latency  of  response,  11 

Respiratory      exchange,      in 
small  animals,  46 

Reymond,  du  Bois,  113 

Ringer,  Sidney,  66 

Rosenthal,  6 

Rubner,  83,  108 

Ryffel,  41,  SO 

Salivary  secretion,  68,  69 
Salts,  aggregation  of  haemo- 
globin by,  31 
passage  into  intestines  af- 
ter water  drinking,  78,  79 
Sampling,  alveolar  air,  8 
Schafer,  Sir  Edward,  17 
method  applied  during  ap- 
noea,  25 
Schmiedeberg,  38 
Schneider,  55 
Scott,  25 
Sea  water,  CO2  pressure  in, 

62 
Secretion,  and  growth,  66 
kidney,  64,  65,  79,  89 
of  CO2  by  lungs,  57 
salivary,  68,  69 
selective,  by  lungs,  62 
Secretion  of  oxygen,  at  high 
altitudes,  56 
by  lung  epithelium,  53,  54, 

57 
by  lungs,  53,  54 


in  swim  bladder  of  fishes, 
62,  63,  64 

Secreting  cells,  synthesis  by, 
65 

"Shock,"  CO2  deficiency  in, 
15,  42,  43 

Sivel,  44 

Smith,  Lorrain,  52,  53,  57 

Sodium  chloride  in  urine, 
after  large  intake  of 
water,  78 

Specific  "structure"  and  com- 
position of  blood,  90,  91 

Starvation,  oxidation  in,  84 

Starvation,  oxygen  consump- 
tion in,  4,  83 

Steel  chamber  experiments, 
49,  50 

Structure,  "normal,"  101 

Sugar  contents  of  blood,  76, 
77 

Suprarenal  glands,  and  vaso- 
constriction, 75 
in  physiological  regulation, 
80 

Surgery  and  physiology,  94 

Sweating,    effects    on    blood 
concentration,  79 
effects    on   blood   constitu- 
ents, 79 
effects  on  urine  secretion, 
79 

Swim  bladder  of  fishes,  ef- 
fects of  drugs  on  oxygen 
secretion  of,  63 
function  of,  62,  63 


INDEX 


137 


nervous  control  of  oxygen 

secretion  in,  63 
reversal    of     direction     of 

oxygen  secretion  in,  64 
structure,  63 
Sympathetic  nerves,  to  heart, 

73 
Symptoms  of  CO  poisoning, 

48 
oxygen  deficiency,  42,  43 

Temperature    regulation,    80, 
89 
in  dog,  by  respiration,  13 

Teneriffe,  Peak  of,  50 

Test  for  presence  of  CO  in 
air,  46 

Thyroid  in  physiological  reg- 
ulation, 80 

Tissandier,  44 

Unconscious  activities,  1 
Urea,  39 

Urea  excretion,  83 
in  starvation,  83 
Urine,  "buffer  substances"  in 
40 
lactic  acid  in,  41 
nitrogen    of,    as    index    of 

blood  alkalinity,  39 
reaction  of,  40 
secretion,   effect   of   sweat- 
ing on,  79 
sodium    chloride   of,    after 
large  intake  of  water,  78 


Vagus  apnoea,  22 
Vagus  nerves,  effect  of  cut- 
ting on  breathing,  21,  25, 
26 
influence  on  breathing,  21, 

22,  23,  24,  26 
to  heart,  73 
Vapour  pressure,   in   alveoli, 

13,  14 
Vaso-construction,    chemical, 
70 
nervous,  70 
regulation       by       adrenal 

glands,  75 
regulation     of     circulation 
rate  by,  72 
Vaso-motor  center,  70 
control  of  local  blood  sup- 
ply by  subordinate,  70 
Vaso-motor  nerves,  70 
Veins,   regulation   of   venous 
pressure    by    contraction 
of  peripheral,  74 
Venous  constriction,  in  rela- 
tion to  CO2  contents  of 
blood,  74,  75 
Venous  gas  pressure,  71,  72 

regulation  of,  72 
Venous    pressure,    effect    on 
accelerator  nerve,  73,  74 
in     regulation     of     output 

from  heart,  74 
regulation  by  CO2  contents 

of  blood,  74,  75 
regulation  by  passive  con- 
gestion of  capillaries,  75 


138 


INDEX 


regulation     by     peripheral 
constriction  of  peripheral 
veins,  74 
Ventilation  in  mines,  19 
Vicarious  function,  97 
"Vital  force,"  110 
"Vital  mechanisms,"  77 
"Vital    principle,"    2,    4,    82, 

110,  112 
"Vital  spirit,"  110 
Vitalism,  2,  4,  82,  87,  110,  112, 
113 
and   regulation   of   breath- 
ing, 17 
Vitalistic  theory,  111 

of  regulation,  4 
Vitiated  air,  18 


Voluntary  control  of  respira- 
tion, 11 
Von  Baer,  3 
Von  Bezold,  73 

Water  excretion,  77 

Water      intake,      effect      on 

haemoglobin    percentage, 

78 
effect  on  kidney  secretion, 

79 
effect   on   sodium  chloride 

of  urine,  78 
Water    regulation    in    blood, 

77,  78,  79 
Weber  brothers,  73 
Wollin,  25 


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